View source for 8zmt


==Cryo-EM structure of Saccharomyces cerevisiae bc1 complex in Metyltetraprole-bound state==
<StructureSection load='8zmt' size='340' side='right'caption='[[8zmt]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8zmt]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8ZMT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ZMT FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.52&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6PH:(1R)-2-(PHOSPHONOOXY)-1-[(TRIDECANOYLOXY)METHYL]ETHYL+PENTADECANOATE'>6PH</scene>, <scene name='pdbligand=8PE:(2R)-3-{[(S)-(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-2-(TETRADECANOYLOXY)PROPYL+OCTADECANOATE'>8PE</scene>, <scene name='pdbligand=9PE:(1R)-2-{[(S)-(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(HEPTANOYLOXY)METHYL]ETHYL+OCTADECANOATE'>9PE</scene>, <scene name='pdbligand=A1D6P:1-[2-[[1-(4-chlorophenyl)pyrazol-3-yl]oxymethyl]-3-methyl-phenyl]-4-methyl-1,2,3,4-tetrazol-5-one'>A1D6P</scene>, <scene name='pdbligand=CN3:(2R,5S,11R,14R)-5,8,11-TRIHYDROXY-2-(NONANOYLOXY)-5,11-DIOXIDO-16-OXO-14-[(PROPANOYLOXY)METHYL]-4,6,10,12,15-PENTAOXA-5,11-DIPHOSPHANONADEC-1-YL+UNDECANOATE'>CN3</scene>, <scene name='pdbligand=CN5:(5S,11R)-5,8,11-TRIHYDROXY-5,11-DIOXIDO-17-OXO-4,6,10,12,16-PENTAOXA-5,11-DIPHOSPHAOCTADEC-1-YL+PENTADECANOATE'>CN5</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=UQ6:5-(3,7,11,15,19,23-HEXAMETHYL-TETRACOSA-2,6,10,14,18,22-HEXAENYL)-2,3-DIMETHOXY-6-METHYL-BENZENE-1,4-DIOL'>UQ6</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=8zmt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8zmt OCA], [https://pdbe.org/8zmt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8zmt RCSB], [https://www.ebi.ac.uk/pdbsum/8zmt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8zmt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A0G3F5W7_YEASX A0A0G3F5W7_YEASX] Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain. The b-c1 complex mediates electron transfer from ubiquinol to cytochrome c. Contributes to the generation of a proton gradient across the mitochondrial membrane that is then used for ATP synthesis.[RuleBase:RU362117]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cytochrome bc(1) (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (Q(o)I) that combats the G143A mutated isolate, which confers high resistance to strobilurin fungicides such as pyraclostrobin (PYR). The binding mode and antiresistance mechanism of MET remain unclear. Here, we determined the high-resolution structures of inhibitor-bound S. cerevisiae complex III (MET, 2.52 A; PYR, 2.42 A) and inhibitor-bound porcine complex III (MET, 2.53 A; PYR, 2,37 A) by cryo-electron microscopy. The distinct binding modes of MET and PYR were observed for the first time. Notably, the MET exhibited different binding modes in the two species. In S. cerevisiae, the binding site of MET was the same as PYR, serving as a Pm-type inhibitor of the Q(o) site. However, in porcine, MET acted as a dual-target inhibitor of both Q(o) and Q(i). Based on the structural insights, a novel inhibitor (YF23694) was discovered and demonstrated excellent fungicidal activity against downy mildew and powdery mildew fungi. This work provides a new starting point for the design of the next generation of inhibitors to overcome the resistance.

Cryo-EM Structures Reveal the Unique Binding Modes of Metyltetraprole in Yeast and Porcine Cytochrome bc(1) Complex Enabling Rational Design of Inhibitors.,Wang YX, Ye Y, Li ZW, Cui GR, Shi XX, Dong Y, Jiang JJ, Sun JY, Guan ZW, Zhang N, Wu QY, Wang F, Zhu XL, Yang GF J Am Chem Soc. 2024 Dec 11;146(49):33903-33913. doi: 10.1021/jacs.4c12595. Epub , 2024 Nov 27. PMID:39601138<ref>PMID:39601138</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8zmt" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Saccharomyces cerevisiae]]
[[Category: Li ZW]]
[[Category: Yang GF]]
[[Category: Ye Y]]