4d6t: Difference between revisions

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-'''Unreleased structure'''
-The entry 4d6t is ON HOLD
+==Cytochrome bc1 bound to the 4(1H)-pyridone GW844520==
+<StructureSection load='4d6t' size='340' side='right'caption='[[4d6t]], [[Resolution|resolution]] 3.57&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4d6t]] is a 19 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D6T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D6T FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.57&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4X9:3-CHLORO-2,6-DIMETHYL-5-{4-[4-(TRIFLUOROMETHOXY)PHENOXY]PHENYL}PYRIDIN-4-OL'>4X9</scene>, <scene name='pdbligand=CDL:CARDIOLIPIN'>CDL</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEC:HEME+C'>HEC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PEE:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>PEE</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4d6t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d6t OCA], [https://pdbe.org/4d6t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d6t RCSB], [https://www.ebi.ac.uk/pdbsum/4d6t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d6t ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/QCR1_BOVIN QCR1_BOVIN] This is a component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is part of the mitochondrial respiratory chain. This protein may mediate formation of the complex between cytochromes c and c1.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Cytochrome bc1 is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Qo site (one of two potential binding sites within cytochrome bc1) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc1 complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Qo site but bind at the Qi site. The discovery that these compounds bind at the Qi site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Qi also explains the ability of this class to overcome parasite Qo-based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles.
-Authors: Capper, M.J., ONeill, P.M., Fisher, N., Strange, R.W., Moss, D., Ward, S.A., Berry, N.G., Lawrenson, A.S., Hasnain, S.S., Biagini, G.A., Antonyuk, S.V.
+Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1.,Capper MJ, O'Neill PM, Fisher N, Strange RW, Moss D, Ward SA, Berry NG, Lawrenson AS, Hasnain SS, Biagini GA, Antonyuk SV Proc Natl Acad Sci U S A. 2015 Jan 6. pii: 201416611. PMID:25564664<ref>PMID:25564664</ref>
-Description: Cytochrome bc1 bound to the 4(1H)-pyridone GW844520
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Lawrenson, A.S]]
+<div class="pdbe-citations 4d6t" style="background-color:#fffaf0;"></div>
-[[Category: Fisher, N]]
+== References ==
-[[Category: Berry, N.G]]
+<references/>
-[[Category: Capper, M.J]]
+__TOC__
-[[Category: Hasnain, S.S]]
+</StructureSection>
-[[Category: Oneill, P.M]]
+[[Category: Bos taurus]]
-[[Category: Biagini, G.A]]
+[[Category: Large Structures]]
-[[Category: Antonyuk, S.V]]
+[[Category: Antonyuk SV]]
-[[Category: Ward, S.A]]
+[[Category: Berry NG]]
-[[Category: Strange, R.W]]
+[[Category: Biagini GA]]
-[[Category: Moss, D]]
+[[Category: Capper MJ]]
+[[Category: Fisher N]]
+[[Category: Hasnain SS]]
+[[Category: Lawrenson AS]]
+[[Category: Moss D]]
+[[Category: O'Neill PM]]
+[[Category: Strange RW]]
+[[Category: Ward SA]]