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10.1038/nsmb.3333 http://scihub22266oqcxt.onion/10.1038/nsmb.3333 C5533293!5533293 !27918545     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\27918545 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Nat+Struct+Mol+Biol 2017 ; 24 (1 ): 69-76 Nephropedia Template TP {{tp|p=27918545 |t=2017. Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer |pdf=|usr=}}{{27918545 }} gab.com Text Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer JO: Nat Struct Mol Biol http://www.kidney.de/pget.php?&tw=1&pmid=27918545 #FOAvip Although warfarin is the most widely used anticoagulant worldwide, the mechanism by which warfarin inhibits its target, human vitamin K epoxide reductase (hVKOR), remains unclear. Here we show that warfarin blocks a dynamic electron-transfer process in hVKOR. A major fraction of cellular hVKOR is in an intermediate redox state containing a Cys51-Cys132 disulfide, a characteristic accommodated by a four-transmembrane-helix structure of hVKOR. Warfarin selectively inhibits this major cellular form of hVKOR, whereas disruption of the Cys51-Cys132 disulfide impairs warfarin binding and causes warfarin resistance. Relying on binding interactions identified by cysteine alkylation footprinting and mass spectrometry coupled with mutagenesis analysis, we conducted structure simulations, which revealed a closed warfarin-binding pocket stabilized by the Cys51-Cys132 linkage. Understanding the selective warfarin inhibition of a specific redox state of hVKOR should enable the rational design of drugs that exploit the redox chemistry and associated conformational changes in hVKOR. Twit Text FOAVip Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer ????Nat Struct Mol Biol http://www.kidney.de/pget.php?&tw=1&pmid=27918545 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=27918545 #FOAvip English Wikipedia <ref>{{Cite pmid|27918545 }}</ref> Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer #MMPMID27918545 Shen G ; Cui W ; Zhang H ; Zhou F ; Huang W ; Liu Q ; Yang Y ; Li S ; Bowman GR ; Sadler JE ; Gross ML ; Li W Nat Struct Mol Biol 2017[Jan]; 24 (1 ): 69-76 PMID27918545 show ga Although warfarin is the most widely used anticoagulant worldwide, the mechanism by which warfarin inhibits its target, human vitamin K epoxide reductase (hVKOR), remains unclear. Here we show that warfarin blocks a dynamic electron-transfer process in hVKOR. A major fraction of cellular hVKOR is in an intermediate redox state containing a Cys51-Cys132 disulfide, a characteristic accommodated by a four-transmembrane-helix structure of hVKOR. Warfarin selectively inhibits this major cellular form of hVKOR, whereas disruption of the Cys51-Cys132 disulfide impairs warfarin binding and causes warfarin resistance. Relying on binding interactions identified by cysteine alkylation footprinting and mass spectrometry coupled with mutagenesis analysis, we conducted structure simulations, which revealed a closed warfarin-binding pocket stabilized by the Cys51-Cys132 linkage. Understanding the selective warfarin inhibition of a specific redox state of hVKOR should enable the rational design of drugs that exploit the redox chemistry and associated conformational changes in hVKOR. |Biocatalysis [MESH] |Catalytic Domain [MESH] |HEK293 Cells [MESH] |Humans [MESH] |Molecular Docking Simulation [MESH] |Oxidation-Reduction [MESH] |Protein Binding [MESH] |Vitamin K 1/analogs & derivatives/chemistry [MESH] |Vitamin K 2/chemistry [MESH] |Vitamin K Epoxide Reductases/antagonists & inhibitors/*chemistry [MESH]Warfarin traps human vitamin K epoxide reductase in an intermediate st(epmc).pdf DeepDyve Pubget Overpricing