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  • 1
    Publication Date: 2018-01-17
    Description: Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear. Experimental Design: We performed in silico screening and in vitro validation studies through Western blotting, qRT-PCR for treatment of WNT and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice. Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacologic blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice. Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation. Clin Cancer Res; 24(2); 383–94. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2011-04-08
    Description: Saccharides have a central role in the nutrition of all living organisms. Whereas several saccharide uptake systems are shared between the different phylogenetic kingdoms, the phosphoenolpyruvate-dependent phosphotransferase system exists almost exclusively in bacteria. This multi-component system includes an integral membrane protein EIIC that transports saccharides and assists in their phosphorylation. Here we present the crystal structure of an EIIC from Bacillus cereus that transports diacetylchitobiose. The EIIC is a homodimer, with an expansive interface formed between the amino-terminal halves of the two protomers. The carboxy-terminal half of each protomer has a large binding pocket that contains a diacetylchitobiose, which is occluded from both sides of the membrane with its site of phosphorylation near the conserved His250 and Glu334 residues. The structure shows the architecture of this important class of transporters, identifies the determinants of substrate binding and phosphorylation, and provides a framework for understanding the mechanism of sugar translocation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201810/" 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/PMC3201810/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cao, Yu -- Jin, Xiangshu -- Levin, Elena J -- Huang, Hua -- Zong, Yinong -- Quick, Matthias -- Weng, Jun -- Pan, Yaping -- Love, James -- Punta, Marco -- Rost, Burkhard -- Hendrickson, Wayne A -- Javitch, Jonathan A -- Rajashankar, Kanagalaghatta R -- Zhou, Ming -- DK088057/DK/NIDDK NIH HHS/ -- GM05026/GM/NIGMS NIH HHS/ -- GM05026-SUB0007/GM/NIGMS NIH HHS/ -- GM098878/GM/NIGMS NIH HHS/ -- K05 DA022413/DA/NIDA NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 GM098878/GM/NIGMS NIH HHS/ -- T32HL087745/HL/NHLBI NIH HHS/ -- England -- Nature. 2011 May 5;473(7345):50-4. doi: 10.1038/nature09939. Epub 2011 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21471968" target="_blank"〉PubMed〈/a〉
    Keywords: Bacillus cereus/*enzymology ; Binding Sites ; Carbohydrate Metabolism ; Crystallization ; Membrane Transport Proteins/*chemistry ; *Models, Molecular ; Phosphorylation ; Protein Structure, Quaternary ; Protein Structure, Tertiary
    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: 2011-02-15
    Description: The TrkH/TrkG/KtrB proteins mediate K(+) uptake in bacteria and probably evolved from simple K(+) channels by multiple gene duplications or fusions. Here we present the crystal structure of a TrkH from Vibrio parahaemolyticus. TrkH is a homodimer, and each protomer contains an ion permeation pathway. A selectivity filter, similar in architecture to those of K(+) channels but significantly shorter, is lined by backbone and side-chain oxygen atoms. Functional studies showed that TrkH is selective for permeation of K(+) and Rb(+) over smaller ions such as Na(+) or Li(+). Immediately intracellular to the selectivity filter are an intramembrane loop and an arginine residue, both highly conserved, which constrict the permeation pathway. Substituting the arginine with an alanine significantly increases the rate of K(+) flux. These results reveal the molecular basis of K(+) selectivity and suggest a novel gating mechanism for this large and important family of membrane transport proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077569/" 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/PMC3077569/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cao, Yu -- Jin, Xiangshu -- Huang, Hua -- Derebe, Mehabaw Getahun -- Levin, Elena J -- Kabaleeswaran, Venkataraman -- Pan, Yaping -- Punta, Marco -- Love, James -- Weng, Jun -- Quick, Matthias -- Ye, Sheng -- Kloss, Brian -- Bruni, Renato -- Martinez-Hackert, Erik -- Hendrickson, Wayne A -- Rost, Burkhard -- Javitch, Jonathan A -- Rajashankar, Kanagalaghatta R -- Jiang, Youxing -- Zhou, Ming -- DK088057/DK/NIDDK NIH HHS/ -- GM05026/GM/NIGMS NIH HHS/ -- GM05026-SUB0007/GM/NIGMS NIH HHS/ -- HL086392/HL/NHLBI NIH HHS/ -- K05 DA022413/DA/NIDA NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 DK088057-01/DK/NIDDK NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- R01 HL086392-05/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 17;471(7338):336-40. doi: 10.1038/nature09731. Epub 2011 Feb 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21317882" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/chemistry ; Amino Acid Sequence ; Crystallography, X-Ray ; Escherichia coli Proteins/chemistry ; Ion Channel Gating ; Ion Transport ; Models, Molecular ; Molecular Sequence Data ; Potassium/metabolism ; Potassium Channels/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Vibrio parahaemolyticus/*chemistry
    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: 2013-04-20
    Description: TrkH belongs to a superfamily of K(+) transport proteins required for growth of bacteria in low external K(+) concentrations. The crystal structure of TrkH from Vibrio parahaemolyticus showed that TrkH resembles a K(+) channel and may have a gating mechanism substantially different from K(+) channels. TrkH assembles with TrkA, a cytosolic protein comprising two RCK (regulate the conductance of K(+)) domains, which are found in certain K(+) channels and control their gating. However, fundamental questions on whether TrkH is an ion channel and how it is regulated by TrkA remain unresolved. Here we show single-channel activity of TrkH that is upregulated by ATP via TrkA. We report two structures of the tetrameric TrkA ring, one in complex with TrkH and one in isolation, in which the ring assumes two markedly different conformations. These results suggest a mechanism for how ATP increases TrkH activity by inducing conformational changes in TrkA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726529/" 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/PMC3726529/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cao, Yu -- Pan, Yaping -- Huang, Hua -- Jin, Xiangshu -- Levin, Elena J -- Kloss, Brian -- Zhou, Ming -- DK088057/DK/NIDDK NIH HHS/ -- GM098878/GM/NIGMS NIH HHS/ -- HL086392/HL/NHLBI NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 GM098878/GM/NIGMS NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM095315/GM/NIGMS NIH HHS/ -- U54GM095315/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Apr 18;496(7445):317-22. doi: 10.1038/nature12056.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23598339" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Bacterial Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; Electric Conductivity ; *Ion Channel Gating ; Ion Transport ; Models, Molecular ; Protein Folding ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Vibrio parahaemolyticus
    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: 2015-08-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Ling -- Chen, Xiang-Jun -- Zhu, Jie -- Xi, Yi-Bo -- Yang, Xu -- Hu, Li-Dan -- Ouyang, Hong -- Patel, Sherrina H -- Jin, Xin -- Lin, Danni -- Wu, Frances -- Flagg, Ken -- Cai, Huimin -- Li, Gen -- Cao, Guiqun -- Lin, Ying -- Chen, Daniel -- Wen, Cindy -- Chung, Christopher -- Wang, Yandong -- Qiu, Austin -- Yeh, Emily -- Wang, Wenqiu -- Hu, Xun -- Grob, Seanna -- Abagyan, Ruben -- Su, Zhiguang -- Tjondro, Harry Christianto -- Zhao, Xi-Juan -- Luo, Hongrong -- Hou, Rui -- Perry, J Jefferson P -- Gao, Weiwei -- Kozak, Igor -- Granet, David -- Li, Yingrui -- Sun, Xiaodong -- Wang, Jun -- Zhang, Liangfang -- Liu, Yizhi -- Yan, Yong-Bin -- Zhang, Kang -- England -- Nature. 2015 Oct 22;526(7574):595. doi: 10.1038/nature15253. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308894" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2015-07-23
    Description: The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Ling -- Chen, Xiang-Jun -- Zhu, Jie -- Xi, Yi-Bo -- Yang, Xu -- Hu, Li-Dan -- Ouyang, Hong -- Patel, Sherrina H -- Jin, Xin -- Lin, Danni -- Wu, Frances -- Flagg, Ken -- Cai, Huimin -- Li, Gen -- Cao, Guiqun -- Lin, Ying -- Chen, Daniel -- Wen, Cindy -- Chung, Christopher -- Wang, Yandong -- Qiu, Austin -- Yeh, Emily -- Wang, Wenqiu -- Hu, Xun -- Grob, Seanna -- Abagyan, Ruben -- Su, Zhiguang -- Tjondro, Harry Christianto -- Zhao, Xi-Juan -- Luo, Hongrong -- Hou, Rui -- Perry, J Jefferson P -- Gao, Weiwei -- Kozak, Igor -- Granet, David -- Li, Yingrui -- Sun, Xiaodong -- Wang, Jun -- Zhang, Liangfang -- Liu, Yizhi -- Yan, Yong-Bin -- Zhang, Kang -- England -- Nature. 2015 Jul 30;523(7562):607-11. doi: 10.1038/nature14650. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; BGI-Shenzhen, Shenzhen 518083, China. ; 1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. ; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] CapitalBio Genomics Co., Ltd., Dongguan 523808, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA. ; Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA. ; King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia. ; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [4] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA [5] Veterans Administration Healthcare System, San Diego, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200341" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Amino Acid Sequence ; Amyloid/chemistry/drug effects/metabolism/ultrastructure ; Animals ; Base Sequence ; Cataract/congenital/*drug therapy/genetics/*metabolism/pathology ; Cell Line ; Child ; Crystallins/chemistry/genetics/metabolism/ultrastructure ; Dogs ; Female ; Humans ; Lanosterol/administration & dosage/*pharmacology/*therapeutic use ; Lens, Crystalline/drug effects/metabolism/pathology ; Male ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/genetics/metabolism/ultrastructure ; Pedigree ; Protein Aggregates/*drug effects ; Protein Aggregation, Pathological/*drug therapy/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2011-01-22
    Description: A sexually mature individual of Darwinopterus preserved together with an egg from the Jurassic of China provides direct evidence of gender in pterosaurs and insights into the reproductive biology of these extinct fliers. This new find and several other examples of Darwinopterus demonstrate that males of this pterosaur had a relatively small pelvis and a large cranial crest, whereas females had a relatively large pelvis and no crest. The ratio of egg mass to adult mass is relatively low, as in extant reptiles, and is comparable to values for squamates. A parchment-like eggshell points to burial and significant uptake of water after oviposition. This evidence for low parental investment contradicts the widespread assumption that reproduction in pterosaurs was like that of birds and shows that it was essentially like that of reptiles.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Junchang -- Unwin, David M -- Deeming, D Charles -- Jin, Xingsheng -- Liu, Yongqing -- Ji, Qiang -- New York, N.Y. -- Science. 2011 Jan 21;331(6015):321-4. doi: 10.1126/science.1197323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Geology, Chinese Academy of Geological Sciences, Beijing 100037, China. lujc2008@126.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21252343" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone and Bones/anatomy & histology ; China ; Egg Shell ; Female ; *Fossils ; Male ; Oviposition ; *Ovum ; Pelvis/anatomy & histology ; Phylogeny ; *Reproduction ; Reptiles/*anatomy & histology/classification/*physiology ; Sex Characteristics
    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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  • 8
    Publication Date: 2018-08-10
    Description: Vitamin K epoxide reductase (VKOR), an endoplasmic reticulum membrane protein, is the key enzyme for vitamin K–dependent carboxylation, a posttranslational modification that is essential for the biological functions of coagulation factors. VKOR is the target of the most widely prescribed oral anticoagulant, warfarin. However, the topological structure of VKOR and the mechanism of warfarin’s inhibition of VKOR remain elusive. Additionally, it is not clear why warfarin-resistant VKOR mutations identified in patients significantly decrease warfarin’s binding affinity, but have only a minor effect on vitamin K binding. Here, we used immunofluorescence confocal imaging of VKOR in live mammalian cells and PEGylation of VKOR’s endogenous cytoplasmic-accessible cysteines in intact microsomes to probe the membrane topology of human VKOR. Our results show that the disputed loop sequence between the first and second transmembrane (TM) domain of VKOR is located in the cytoplasm, supporting a 3-TM topological structure of human VKOR. Using molecular dynamics (MD) simulations, a T-shaped stacking interaction between warfarin and tyrosine residue 139, within the proposed TY 139 A warfarin-binding motif, was observed. Furthermore, a reversible dynamic warfarin-binding pocket opening and conformational changes were observed when warfarin binds to VKOR. Several residues (Y25, A26, and Y139) were found essential for warfarin binding to VKOR by MD simulations, and these were confirmed by the functional study of VKOR and its mutants in their native milieu using a cell-based assay. Our findings provide new insights into the dynamics of the binding of warfarin to VKOR, as well as into warfarin’s mechanism of anticoagulation.
    Keywords: Thrombosis and Hemostasis
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 9
    Publication Date: 2018-06-21
    Description: Hierarchical carbon nanofibre (CNF)/SnO 2 /Ni nanostructures of graphitized carbon nanofibres and SnO 2 nanocrystallines and Ni nanocrystallines have been prepared via divalent tin–alginate assembly on polyacrylonitrile (PAN) fibres, controlled pyrolysis and ball milling. Fabrication is implemented in three steps: (1) formation of a tin–alginate layer on PAN fibres by coating sodium alginate on PAN in a water medium followed by polycondensation in SnCl 2 solution; (2) heat treatment at 450°C in a nitrogen atmosphere; (3) ball milling the mixture of CNF/SnO 2 fibres and Ni powder. The CNF/SnO 2 /Ni nanocomposite exhibits good lithium ion storage capacity and cyclability, providing a facile and low-cost approach for the large-scale preparation of anode materials for lithium ion batteries.
    Keywords: materials science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 10
    Publication Date: 2018-06-27
    Description: The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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