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| | <StructureSection load='4d6u' size='340' side='right'caption='[[4d6u]], [[Resolution|resolution]] 4.09Å' scene=''> | | <StructureSection load='4d6u' size='340' side='right'caption='[[4d6u]], [[Resolution|resolution]] 4.09Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4d6u]] is a 20 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D6U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D6U FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4d6u]] is a 17 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=4D6U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D6U FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CDL:CARDIOLIPIN'>CDL</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=G8U:3-CHLORO-6-(HYDROXYMETHYL)-2-METHYL-5-{4-[3-(TRIFLUOROMETHOXY)PHENOXY]PHENYL}PYRIDIN-4-OL'>G8U</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> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CDL:CARDIOLIPIN'>CDL</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=G8U:3-CHLORO-6-(HYDROXYMETHYL)-2-METHYL-5-{4-[3-(TRIFLUOROMETHOXY)PHENOXY]PHENYL}PYRIDIN-4-OL'>G8U</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4d6t|4d6t]]</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=4d6u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d6u OCA], [https://pdbe.org/4d6u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d6u RCSB], [https://www.ebi.ac.uk/pdbsum/4d6u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d6u ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ubiquinol--cytochrome-c_reductase Ubiquinol--cytochrome-c reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.10.2.2 1.10.2.2] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4d6u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d6u OCA], [http://pdbe.org/4d6u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d6u RCSB], [http://www.ebi.ac.uk/pdbsum/4d6u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4d6u ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/QCR7_BOVIN QCR7_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 component is involved in redox-linked proton pumping. [[http://www.uniprot.org/uniprot/QCR2_BOVIN QCR2_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. The core protein 2 is required for the assembly of the complex. [[http://www.uniprot.org/uniprot/CYB_BOVIN CYB_BOVIN]] Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is a respiratory chain that generates an electrochemical potential coupled to ATP synthesis. [[http://www.uniprot.org/uniprot/QCR8_BOVIN QCR8_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 subunit, together with cytochrome b, binds to ubiquinone. [[http://www.uniprot.org/uniprot/QCR9_BOVIN QCR9_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 subunit interacts with cytochrome c1. [[http://www.uniprot.org/uniprot/UCRI_BOVIN UCRI_BOVIN]] Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is a respiratory chain that generates an electrochemical potential coupled to ATP synthesis. The transit peptide of the Rieske protein seems to form part of the bc1 complex and is considered to be the subunit 11/IX of that complex. [[http://www.uniprot.org/uniprot/QCR6_BOVIN QCR6_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. [[http://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. [[http://www.uniprot.org/uniprot/CY1_BOVIN CY1_BOVIN]] This is the heme-containing component of the cytochrome b-c1 complex, which accepts electrons from Rieske protein and transfers electrons to cytochrome c in the mitochondrial respiratory chain. | + | [[https://www.uniprot.org/uniprot/QCR2_BOVIN QCR2_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. The core protein 2 is required for the assembly of the complex. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | [[Category: Bos taurus]] | | [[Category: Bos taurus]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ubiquinol--cytochrome-c reductase]]
| + | [[Category: Antonyuk SV]] |
| - | [[Category: Antonyuk, S V]] | + | [[Category: Berry NG]] |
| - | [[Category: Berry, N G]] | + | [[Category: Biagini GA]] |
| - | [[Category: Biagini, G A]] | + | [[Category: Capper MJ]] |
| - | [[Category: Capper, M J]] | + | [[Category: Fisher N]] |
| - | [[Category: Fisher, N]] | + | [[Category: Hasnain SS]] |
| - | [[Category: Hasnain, S S]] | + | [[Category: Lawrenson AS]] |
| - | [[Category: Lawrenson, A S]] | + | [[Category: Moss D]] |
| - | [[Category: Moss, D]] | + | [[Category: ONeill PM]] |
| - | [[Category: ONeill, P M]] | + | [[Category: Strange RW]] |
| - | [[Category: Strange, R W]] | + | [[Category: Ward SA]] |
| - | [[Category: Ward, S A]] | + | |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
4d6u is a 17 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[QCR2_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. The core protein 2 is required for the assembly of the complex.
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Capper MJ, O'Neill PM, Fisher N, Strange RW, Moss D, Ward SA, Berry NG, Lawrenson AS, Hasnain SS, Biagini GA, Antonyuk SV. Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1. Proc Natl Acad Sci U S A. 2015 Jan 6. pii: 201416611. PMID:25564664 doi:http://dx.doi.org/10.1073/pnas.1416611112
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