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  • 1
    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
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    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
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-05-03
    Description: The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 A resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657389/" 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/PMC3657389/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Chong -- Wu, Huixian -- Katritch, Vsevolod -- Han, Gye Won -- Huang, Xi-Ping -- Liu, Wei -- Siu, Fai Yiu -- Roth, Bryan L -- Cherezov, Vadim -- Stevens, Raymond C -- F32 DK088392/DK/NIDDK NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- R01 DA27170/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- R01MH61887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- U19 MH82441/MH/NIMH NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 May 16;497(7449):338-43. doi: 10.1038/nature12167. Epub 2013 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational 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/23636324" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Antineoplastic Agents/*chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Disulfides/chemistry ; Frizzled Receptors/chemistry/classification ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Phthalazines/*chemistry/metabolism ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/*chemistry/classification/metabolism ; Structural Homology, Protein
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-11-10
    Description: At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Xi-Ping -- Karpiak, Joel -- Kroeze, Wesley K -- Zhu, Hu -- Chen, Xin -- Moy, Sheryl S -- Saddoris, Kara A -- Nikolova, Viktoriya D -- Farrell, Martilias S -- Wang, Sheng -- Mangano, Thomas J -- Deshpande, Deepak A -- Jiang, Alice -- Penn, Raymond B -- Jin, Jian -- Koller, Beverly H -- Kenakin, Terry -- Shoichet, Brian K -- Roth, Bryan L -- GM59957/GM/NIGMS NIH HHS/ -- GM71896/GM/NIGMS NIH HHS/ -- P01 HL114471/HL/NHLBI NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- U01 MH104974/MH/NIMH NIH HHS/ -- U19MH082441/MH/NIMH NIH HHS/ -- U54 HD079124/HD/NICHD NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):477-83. doi: 10.1038/nature15699. Epub 2015 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7365, USA. ; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA. ; Department of Pharmaceutical Chemistry, University of California at San Francisco, Byers Hall, 1700 4th Street, San Francisco, California 94158-2550, USA. ; Center for Integrative Chemical Biology and Drug Discovery (CICBDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7363, USA. ; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA. ; Department of Psychiatry and Carolina Institute for Developmental Disabilities (CIDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7146, USA. ; Center for Translational Medicine and Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. ; Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7264, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26550826" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Allosteric Site ; Animals ; Anti-Anxiety Agents/analysis/chemistry/metabolism/pharmacology ; Benzyl Alcohols/analysis/*chemistry/metabolism/*pharmacology ; Conditioning, Classical ; *Drug Discovery ; Fear ; Female ; HEK293 Cells ; Humans ; Ligands ; Lorazepam/analysis/*chemistry/metabolism/*pharmacology ; Male ; Memory/drug effects ; Mice ; Mice, Knockout ; Models, Molecular ; Receptors, G-Protein-Coupled/agonists/antagonists & ; inhibitors/chemistry/deficiency/*metabolism ; Signal Transduction/drug effects ; Triazines/analysis/*chemistry/metabolism/*pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2012-03-24
    Description: We investigated the effect of activating a competing, artificially generated, neural representation on encoding of contextual fear memory in mice. We used a c-fos-based transgenic approach to introduce the hM(3)D(q) DREADD receptor (designer receptor exclusively activated by designer drug) into neurons naturally activated by sensory experience. Neural activity could then be specifically and inducibly increased in the hM(3)D(q)-expressing neurons by an exogenous ligand. When an ensemble of neurons for one context (ctxA) was artificially activated during conditioning in a distinct second context (ctxB), mice formed a hybrid memory representation. Reactivation of the artificially stimulated network within the conditioning context was required for retrieval of the memory, and the memory was specific for the spatial pattern of neurons artificially activated during learning. Similar stimulation impaired recall when not part of the initial conditioning.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956300/" 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/PMC3956300/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garner, Aleena R -- Rowland, David C -- Hwang, Sang Youl -- Baumgaertel, Karsten -- Roth, Bryan L -- Kentros, Cliff -- Mayford, Mark -- R01 DA028300/DA/NIDA NIH HHS/ -- R01 DA028300-04/DA/NIDA NIH HHS/ -- R01 MH057368/MH/NIMH NIH HHS/ -- R01 MH057368-14/MH/NIMH NIH HHS/ -- R01DA028300/DA/NIDA NIH HHS/ -- R01MH057368/MH/NIMH NIH HHS/ -- U19MH82441/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2012 Mar 23;335(6075):1513-6. doi: 10.1126/science.1214985.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22442487" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/physiology ; Animals ; Behavior, Animal ; Brain/*physiology ; CA1 Region, Hippocampal/physiopathology ; Clozapine/analogs & derivatives/pharmacology ; Conditioning (Psychology) ; Cues ; Electroshock ; *Fear ; Genes, fos ; Learning ; *Memory ; Mental Recall ; Mice ; Mice, Transgenic ; Nerve Net/physiology ; Neurons/*physiology ; Promoter Regions, Genetic ; Receptor, Muscarinic M3/genetics/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2013-03-23
    Description: Drugs active at G protein-coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for beta-arrestin signaling at the 5-HT2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT2B receptor bound to ERG and compared it with the 5-HT1B/ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644390/" 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/PMC3644390/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wacker, Daniel -- Wang, Chong -- Katritch, Vsevolod -- Han, Gye Won -- Huang, Xi-Ping -- Vardy, Eyal -- McCorvy, John D -- Jiang, Yi -- Chu, Meihua -- Siu, Fai Yiu -- Liu, Wei -- Xu, H Eric -- Cherezov, Vadim -- Roth, Bryan L -- Stevens, Raymond C -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 DK071662/DK/NIDDK NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- R01 MH61887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- U19 MH82441/MH/NIMH NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 May 3;340(6132):615-9. doi: 10.1126/science.1232808. Epub 2013 Mar 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23519215" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Arrestin/metabolism ; Arrestins/metabolism ; Binding Sites ; Crystallography, X-Ray ; Ergolines/chemistry/metabolism ; Ergotamine/chemistry/*metabolism ; HEK293 Cells ; Humans ; Ligands ; Lysergic Acid Diethylamide/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Protein Structure, Secondary ; Receptor, Serotonin, 5-HT1B/chemistry/*metabolism ; Receptor, Serotonin, 5-HT2B/*chemistry/*metabolism ; Receptors, Serotonin/chemistry/metabolism ; Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    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
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2012-12-12
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roth, Bryan L -- Marshall, Fiona H -- England -- Nature. 2012 Dec 6;492(7427):57. doi: 10.1038/492057a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23222609" target="_blank"〉PubMed〈/a〉
    Keywords: Biochemistry/history ; *Chemistry/history ; Drug Discovery/history ; High-Throughput Screening Assays/history ; History, 20th Century ; History, 21st Century ; Humans ; *Nobel Prize ; Receptors, G-Protein-Coupled/genetics/isolation & purification/*metabolism ; Structure-Activity Relationship
    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: 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
    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: 2014-01-15
    Description: Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 A high-resolution crystal structure of the human delta-opioid receptor (delta-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive delta-OR sodium ion site architecture is centrally located in a polar interaction network in the seven-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn 131 to an alanine or a valine augments constitutive beta-arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical delta-opioid antagonists such as naltrindole into potent beta-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G-protein-coupled receptor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931418/" 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/PMC3931418/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fenalti, Gustavo -- Giguere, Patrick M -- Katritch, Vsevolod -- Huang, Xi-Ping -- Thompson, Aaron A -- Cherezov, Vadim -- Roth, Bryan L -- Stevens, Raymond C -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Feb 13;506(7487):191-6. doi: 10.1038/nature12944. Epub 2014 Jan 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2]. ; 1] National Institute of Mental Health Psychoactive Drug Screening Program and Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA [2]. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; National Institute of Mental Health Psychoactive Drug Screening Program and Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24413399" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects/genetics ; Allosteric Site/drug effects/genetics ; Arrestins/metabolism ; Asparagine/genetics/metabolism ; Crystallography, X-Ray ; Humans ; Ligands ; Models, Molecular ; Mutagenesis, Site-Directed ; Naltrexone/analogs & derivatives/chemistry/metabolism/pharmacology ; Narcotic Antagonists/chemistry/metabolism/pharmacology ; Receptors, Opioid, delta/agonists/antagonists & ; inhibitors/*chemistry/genetics/*metabolism ; *Signal Transduction/drug effects ; Sodium/metabolism/pharmacology ; Structure-Activity Relationship
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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