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  • Female  (20)
  • Crystallography, X-Ray  (9)
  • Substrate Specificity  (5)
  • Nature Publishing Group (NPG)  (32)
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  • 1
    Publication Date: 2016-03-17
    Description: CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851431/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851431/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Wei -- Bai, Yibing -- Xiong, Ying -- Zhang, Jin -- Chen, Shuokai -- Zheng, Xiaojun -- Meng, Xiangbo -- Li, Lunyi -- Wang, Jing -- Xu, Chenguang -- Yan, Chengsong -- Wang, Lijuan -- Chang, Catharine C Y -- Chang, Ta-Yuan -- Zhang, Ti -- Zhou, Penghui -- Song, Bao-Liang -- Liu, Wanli -- Sun, Shao-cong -- Liu, Xiaolong -- Li, Bo-liang -- Xu, Chenqi -- HL 60306./HL/NHLBI NIH HHS/ -- R01 HL060306/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Mar 31;531(7596):651-5. doi: 10.1038/nature17412. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; MOE Key Laboratory of Protein Science, School of Life Sciences, Collaborative Innovation Center for Infectious Diseases, Tsinghua University, Beijing 100084, China. ; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Haven 03755, USA. ; Rheumatology and Immunology Department of ChangZheng Hospital, Second Military Medical University, Shanghai 200433, China. ; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. ; College of Life Sciences, Wuhan University, Wuhan, Hubei Province 430072, China. ; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. ; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982734" target="_blank"〉PubMed〈/a〉
    Keywords: Acetates/*pharmacology/therapeutic use ; Acetyl-CoA C-Acetyltransferase/antagonists & ; inhibitors/deficiency/genetics/metabolism ; Animals ; Atherosclerosis/drug therapy ; CD8-Positive T-Lymphocytes/*drug effects/*immunology/metabolism ; Cell Membrane/drug effects/metabolism ; Cholesterol/*metabolism ; Esterification/drug effects ; Female ; Immunological Synapses/drug effects/immunology/metabolism ; Immunotherapy/*methods ; Male ; Melanoma/*drug therapy/*immunology/metabolism/pathology ; Mice ; Programmed Cell Death 1 Receptor/antagonists & inhibitors/immunology ; Receptors, Antigen, T-Cell/immunology/metabolism ; Signal Transduction/drug effects ; Sulfonic Acids/*pharmacology/therapeutic use
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-08-26
    Description: Genetic manipulations of insect populations for pest control have been advocated for some time, but there are few cases where manipulated individuals have been released in the field and no cases where they have successfully invaded target populations. Population transformation using the intracellular bacterium Wolbachia is particularly attractive because this maternally-inherited agent provides a powerful mechanism to invade natural populations through cytoplasmic incompatibility. When Wolbachia are introduced into mosquitoes, they interfere with pathogen transmission and influence key life history traits such as lifespan. Here we describe how the wMel Wolbachia infection, introduced into the dengue vector Aedes aegypti from Drosophila melanogaster, successfully invaded two natural A. aegypti populations in Australia, reaching near-fixation in a few months following releases of wMel-infected A. aegypti adults. Models with plausible parameter values indicate that Wolbachia-infected mosquitoes suffered relatively small fitness costs, leading to an unstable equilibrium frequency 〈30% that must be exceeded for invasion. These findings demonstrate that Wolbachia-based strategies can be deployed as a practical approach to dengue suppression with potential for area-wide implementation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoffmann, A A -- Montgomery, B L -- Popovici, J -- Iturbe-Ormaetxe, I -- Johnson, P H -- Muzzi, F -- Greenfield, M -- Durkan, M -- Leong, Y S -- Dong, Y -- Cook, H -- Axford, J -- Callahan, A G -- Kenny, N -- Omodei, C -- McGraw, E A -- Ryan, P A -- Ritchie, S A -- Turelli, M -- O'Neill, S L -- England -- Nature. 2011 Aug 24;476(7361):454-7. doi: 10.1038/nature10356.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Bio21 Institute, Department of Genetics, The University of Melbourne, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21866160" target="_blank"〉PubMed〈/a〉
    Keywords: Aedes/*microbiology/physiology/*virology ; Animals ; Dengue/microbiology/*prevention & control/*transmission/virology ; Dengue Virus/isolation & purification/*physiology ; Drosophila melanogaster/microbiology ; Female ; Humans ; Insect Vectors/microbiology/physiology/virology ; Male ; Pest Control, Biological/*methods ; Queensland ; Time Factors ; Wolbachia/isolation & purification/*physiology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-06-05
    Description: Neural activity during development critically shapes postnatal wiring of the mammalian brain. This is best illustrated by the sensory systems, in which the patterned feed-forward excitation provided by sensory organs and experience drives the formation of mature topographic circuits capable of extracting specific features of sensory stimuli. In contrast, little is known about the role of early activity in the development of the basal ganglia, a phylogenetically ancient group of nuclei fundamentally important for complex motor action and reward-based learning. These nuclei lack direct sensory input and are only loosely topographically organized, forming interlocking feed-forward and feed-back inhibitory circuits without laminar structure. Here we use transgenic mice and viral gene transfer methods to modulate neurotransmitter release and neuronal activity in vivo in the developing striatum. We find that the balance of activity between the two inhibitory and antagonist pathways in the striatum regulates excitatory innervation of the basal ganglia during development. These effects indicate that the propagation of activity through a multi-stage network regulates the wiring of the basal ganglia, revealing an important role of positive feedback in driving network maturation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367801/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367801/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kozorovitskiy, Yevgenia -- Saunders, Arpiar -- Johnson, Caroline A -- Lowell, Bradford B -- Sabatini, Bernardo L -- F31 NS074842/NS/NINDS NIH HHS/ -- F31 NS074842-02/NS/NINDS NIH HHS/ -- NS046579/NS/NINDS NIH HHS/ -- R01 DK089044/DK/NIDDK NIH HHS/ -- R01 NS046579/NS/NINDS NIH HHS/ -- R01 NS046579-09/NS/NINDS NIH HHS/ -- T32 MH020017/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 13;485(7400):646-50. doi: 10.1038/nature11052.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22660328" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basal Ganglia/cytology/*embryology/*physiology ; Cerebral Cortex/cytology/physiology ; Feedback, Physiological ; Female ; Male ; Mice ; Mice, Transgenic ; Models, Neurological ; Neostriatum/cytology/*embryology/*physiology ; Neural Inhibition ; Neural Pathways/*physiology ; Synapses/*metabolism ; Thalamus/cytology/physiology ; Vesicular Inhibitory Amino Acid Transport Proteins/deficiency/genetics/metabolism ; gamma-Aminobutyric Acid/secretion
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2012-12-14
    Description: The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653568/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653568/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Besnard, Jeremy -- Ruda, Gian Filippo -- Setola, Vincent -- Abecassis, Keren -- Rodriguiz, Ramona M -- Huang, Xi-Ping -- Norval, Suzanne -- Sassano, Maria F -- Shin, Antony I -- Webster, Lauren A -- Simeons, Frederick R C -- Stojanovski, Laste -- Prat, Annik -- Seidah, Nabil G -- Constam, Daniel B -- Bickerton, G Richard -- Read, Kevin D -- Wetsel, William C -- Gilbert, Ian H -- Roth, Bryan L -- Hopkins, Andrew L -- 083481/Wellcome Trust/United Kingdom -- BB/FOF/PF/15/09/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/J010510/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MH082441/MH/NIMH NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- WT 083481/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):215-20. doi: 10.1038/nature11691.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235874" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Automation ; Drug Delivery Systems ; *Drug Design ; Female ; *Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Models, Theoretical ; Pharmacological Phenomena ; Reproducibility of Results
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  • 5
    Publication Date: 2011-12-23
    Description: Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A). In neurons, the paternal allele of UBE3A is intact but epigenetically silenced, raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein. Using an unbiased, high-content screen in primary cortical neurons from mice, we identify twelve topoisomerase I inhibitors and four topoisomerase II inhibitors that unsilence the paternal Ube3a allele. These drugs included topotecan, irinotecan, etoposide and dexrazoxane (ICRF-187). At nanomolar concentrations, topotecan upregulated catalytically active UBE3A in neurons from maternal Ube3a-null mice. Topotecan concomitantly downregulated expression of the Ube3a antisense transcript that overlaps the paternal copy of Ube3a. These results indicate that topotecan unsilences Ube3a in cis by reducing transcription of an imprinted antisense RNA. When administered in vivo, topotecan unsilenced the paternal Ube3a allele in several regions of the nervous system, including neurons in the hippocampus, neocortex, striatum, cerebellum and spinal cord. Paternal expression of Ube3a remained elevated in a subset of spinal cord neurons for at least 12 weeks after cessation of topotecan treatment, indicating that transient topoisomerase inhibition can have enduring effects on gene expression. Although potential off-target effects remain to be investigated, our findings suggest a therapeutic strategy for reactivating the functional but dormant allele of Ube3a in patients with Angelman syndrome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257422/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257422/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Hsien-Sung -- Allen, John A -- Mabb, Angela M -- King, Ian F -- Miriyala, Jayalakshmi -- Taylor-Blake, Bonnie -- Sciaky, Noah -- Dutton, J Walter Jr -- Lee, Hyeong-Min -- Chen, Xin -- Jin, Jian -- Bridges, Arlene S -- Zylka, Mark J -- Roth, Bryan L -- Philpot, Benjamin D -- 5F32NS067712/NS/NINDS NIH HHS/ -- 5P30NS045892/NS/NINDS NIH HHS/ -- HHSN-271-2008-00025-C/PHS HHS/ -- P30 HD003110/HD/NICHD NIH HHS/ -- P30 HD003110-45/HD/NICHD NIH HHS/ -- P30HD03110/HD/NICHD NIH HHS/ -- R01EY018323/EY/NEI NIH HHS/ -- R01MH093372/MH/NIMH NIH HHS/ -- R01NS060725/NS/NINDS NIH HHS/ -- R01NS067688/NS/NINDS NIH HHS/ -- T32 HD040127/HD/NICHD NIH HHS/ -- T32 HD040127-10/HD/NICHD NIH HHS/ -- T32HD040127-07/HD/NICHD NIH HHS/ -- England -- Nature. 2011 Dec 21;481(7380):185-9. doi: 10.1038/nature10726.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22190039" target="_blank"〉PubMed〈/a〉
    Keywords: *Alleles ; Angelman Syndrome/drug therapy/genetics ; Animals ; Cells, Cultured ; Cerebral Cortex/cytology/drug effects/metabolism ; Drug Evaluation, Preclinical ; Fathers ; Female ; Gene Silencing/*drug effects ; Genomic Imprinting/drug effects/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mothers ; Neurons/*drug effects/*metabolism ; Small Molecule Libraries/administration & dosage/chemistry/pharmacology ; Topoisomerase Inhibitors/administration & ; dosage/analysis/pharmacokinetics/*pharmacology ; Topotecan/administration & dosage/pharmacokinetics/pharmacology ; Ubiquitin-Protein Ligases/deficiency/*genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2012-03-23
    Description: Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of kappa-opioid receptor (kappa-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human kappa-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 A resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human kappa-OR. Modelling of other important kappa-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for kappa-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human kappa-OR.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356457/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356457/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Huixian -- Wacker, Daniel -- Mileni, Mauro -- Katritch, Vsevolod -- Han, Gye Won -- Vardy, Eyal -- Liu, Wei -- Thompson, Aaron A -- Huang, Xi-Ping -- Carroll, F Ivy -- Mascarella, S Wayne -- Westkaemper, Richard B -- Mosier, Philip D -- Roth, Bryan L -- Cherezov, Vadim -- Stevens, Raymond C -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-08/GM/NIGMS NIH HHS/ -- R01 DA009045/DA/NIDA NIH HHS/ -- R01 DA009045-17/DA/NIDA NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA017624/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54 GM094618-02/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 21;485(7398):327-32. doi: 10.1038/nature10939.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22437504" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Diterpenes, Clerodane/chemistry/metabolism/pharmacology ; Guanidines/chemistry ; Humans ; Models, Molecular ; Morphinans/chemistry ; Mutagenesis, Site-Directed ; Naltrexone/analogs & derivatives/chemistry/metabolism ; Piperidines/*chemistry/pharmacology ; Protein Conformation ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, CXCR4/chemistry/metabolism ; Receptors, Opioid, kappa/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Structure-Activity Relationship ; Tetrahydroisoquinolines/*chemistry/pharmacology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2012-05-19
    Description: Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, delta, kappa and mu (delta-OR, kappa-OR and mu-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes ( approximately 60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors kappa (ref. 5) and mu (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356928/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356928/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thompson, Aaron A -- Liu, Wei -- Chun, Eugene -- Katritch, Vsevolod -- Wu, Huixian -- Vardy, Eyal -- Huang, Xi-Ping -- Trapella, Claudio -- Guerrini, Remo -- Calo, Girolamo -- Roth, Bryan L -- Cherezov, Vadim -- Stevens, Raymond C -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-08/GM/NIGMS NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA017204-08/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- R01 DA027170-03/DA/NIDA NIH HHS/ -- R01 DA27170/DA/NIDA NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54 GM094618-02/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 May 16;485(7398):395-9. doi: 10.1038/nature11085.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22596163" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Biomimetic Materials/*chemistry/metabolism/pharmacology ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Ligands ; Models, Molecular ; Narcotic Antagonists ; Opioid Peptides/*chemistry/metabolism/pharmacology ; Piperidines/*chemistry/*metabolism/pharmacology ; Protein Conformation ; Receptors, Opioid/*chemistry/*metabolism ; Receptors, Opioid, kappa/chemistry/metabolism ; Spiro Compounds/*chemistry/*metabolism/pharmacology ; Substrate Specificity
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2014-10-03
    Description: The CRISPR-associated protein Cas9 is an RNA-guided DNA endonuclease that uses RNA-DNA complementarity to identify target sites for sequence-specific double-stranded DNA (dsDNA) cleavage. In its native context, Cas9 acts on DNA substrates exclusively because both binding and catalysis require recognition of a short DNA sequence, known as the protospacer adjacent motif (PAM), next to and on the strand opposite the twenty-nucleotide target site in dsDNA. Cas9 has proven to be a versatile tool for genome engineering and gene regulation in a large range of prokaryotic and eukaryotic cell types, and in whole organisms, but it has been thought to be incapable of targeting RNA. Here we show that Cas9 binds with high affinity to single-stranded RNA (ssRNA) targets matching the Cas9-associated guide RNA sequence when the PAM is presented in trans as a separate DNA oligonucleotide. Furthermore, PAM-presenting oligonucleotides (PAMmers) stimulate site-specific endonucleolytic cleavage of ssRNA targets, similar to PAM-mediated stimulation of Cas9-catalysed DNA cleavage. Using specially designed PAMmers, Cas9 can be specifically directed to bind or cut RNA targets while avoiding corresponding DNA sequences, and we demonstrate that this strategy enables the isolation of a specific endogenous messenger RNA from cells. These results reveal a fundamental connection between PAM binding and substrate selection by Cas9, and highlight the utility of Cas9 for programmable transcript recognition without the need for tags.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268322/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268322/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O'Connell, Mitchell R -- Oakes, Benjamin L -- Sternberg, Samuel H -- East-Seletsky, Alexandra -- Kaplan, Matias -- Doudna, Jennifer A -- P50 GM102706/GM/NIGMS NIH HHS/ -- P50GM102706-03/GM/NIGMS NIH HHS/ -- T32 GM007232/GM/NIGMS NIH HHS/ -- T32 GM066698/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 11;516(7530):263-6. doi: 10.1038/nature13769. Epub 2014 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Department of Chemistry, University of California, Berkeley, California 94720, USA. ; 1] Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA [2] Department of Agricultural and Biological Engineering, University of Florida, Gainesville, Florida 32611, USA. ; 1] Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA [2] Department of Chemistry, University of California, Berkeley, California 94720, USA [3] Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA [4] Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25274302" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; CRISPR-Associated Proteins/*metabolism ; CRISPR-Cas Systems/*physiology ; Cell Extracts ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; DNA/chemistry/genetics/metabolism ; Genetic Engineering/*methods ; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/genetics ; HeLa Cells ; Humans ; Nucleotide Motifs ; Oligonucleotides/chemistry/genetics/metabolism ; RNA/chemistry/genetics/*metabolism ; RNA, Guide/chemistry/genetics/metabolism ; RNA, Messenger/genetics/isolation & purification/metabolism ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2015-05-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hogan, Benjamin M -- Black, Brian L -- England -- Nature. 2015 Jun 4;522(7554):37-8.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992543" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; *Cell Lineage ; Endothelial Cells/*cytology ; Female ; Humans ; *Lymphangiogenesis ; Lymphatic Vessels/*cytology/*injuries ; Male ; Myocardium/*cytology ; Stem Cells/*cytology ; Veins/*cytology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2016-04-07
    Description: How tissue regeneration programs are triggered by injury has received limited research attention. Here we investigate the existence of enhancer regulatory elements that are activated in regenerating tissue. Transcriptomic analyses reveal that leptin b (lepb) is highly induced in regenerating hearts and fins of zebrafish. Epigenetic profiling identified a short DNA sequence element upstream and distal to lepb that acquires open chromatin marks during regeneration and enables injury-dependent expression from minimal promoters. This element could activate expression in injured neonatal mouse tissues and was divisible into tissue-specific modules sufficient for expression in regenerating zebrafish fins or hearts. Simple enhancer-effector transgenes employing lepb-linked sequences upstream of pro- or anti-regenerative factors controlled the efficacy of regeneration in zebrafish. Our findings provide evidence for 'tissue regeneration enhancer elements' (TREEs) that trigger gene expression in injury sites and can be engineered to modulate the regenerative potential of vertebrate organs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844022/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844022/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Junsu -- Hu, Jianxin -- Karra, Ravi -- Dickson, Amy L -- Tornini, Valerie A -- Nachtrab, Gregory -- Gemberling, Matthew -- Goldman, Joseph A -- Black, Brian L -- Poss, Kenneth D -- F32 HL120494/HL/NHLBI NIH HHS/ -- K08 HL116485/HL/NHLBI NIH HHS/ -- P01 HL089707/HL/NHLBI NIH HHS/ -- R01 GM074057/GM/NIGMS NIH HHS/ -- R01 HL064658/HL/NHLBI NIH HHS/ -- R01 HL081674/HL/NHLBI NIH HHS/ -- R01 HL089707/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Apr 14;532(7598):201-6. doi: 10.1038/nature17644. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143, USA. ; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049946" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animal Fins/injuries/metabolism ; Animals ; Animals, Newborn ; Cell Proliferation ; Chromatin Assembly and Disassembly/genetics ; Enhancer Elements, Genetic/*genetics ; Epigenesis, Genetic/genetics ; Female ; Gene Expression Profiling ; Gene Expression Regulation/genetics ; Heart ; Histones/chemistry/metabolism ; Leptin/biosynthesis/genetics ; Lysine/metabolism ; Male ; Mice ; Myocytes, Cardiac/cytology ; Organ Specificity/*genetics ; Promoter Regions, Genetic/genetics ; Regeneration/*genetics/*physiology ; Transgenes/genetics ; Wound Healing/*genetics ; Zebrafish/*genetics/*physiology ; Zebrafish Proteins/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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