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Structure paper

TitleCryo-EM Structures Reveal the Unique Binding Modes of Metyltetraprole in Yeast and Porcine Cytochrome Complex Enabling Rational Design of Inhibitors.
Journal, issue, pagesJ Am Chem Soc, Vol. 146, Issue 49, Page 33903-33913, Year 2024
Publish dateDec 11, 2024
AuthorsYu-Xia Wang / Ying Ye / Zhi-Wen Li / Guang-Rui Cui / Xing-Xing Shi / Ying Dong / Jia-Jia Jiang / Jia-Yue Sun / Ze-Wei Guan / Nan Zhang / Qiong-You Wu / Fan Wang / Xiao-Lei Zhu / Guang-Fu Yang /
PubMed AbstractCytochrome (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (QI) that combats ...Cytochrome (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (QI) 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 complex III (MET, 2.52 Å; PYR, 2.42 Å) and inhibitor-bound porcine complex III (MET, 2.53 Å; PYR, 2,37 Å) 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 , the binding site of MET was the same as PYR, serving as a -type inhibitor of the Q site. However, in porcine, MET acted as a dual-target inhibitor of both Q and Q. 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.
External linksJ Am Chem Soc / PubMed:39601138
MethodsEM (single particle)
Resolution2.37 - 2.74 Å
Structure data

39291

8yhq

EMDB-39291, PDB-8yhq:
Cryo-EM structure of Saccharomyces cerevisiae bc1 complex in pyraclostrobin-bound state
Method: EM (single particle) / Resolution: 2.42 Å

39323

8yin

EMDB-39323, PDB-8yin:
Cryo-EM structure of Saccharomyces cerevisiae bc1 complex in YF23694-bound state
Method: EM (single particle) / Resolution: 2.74 Å

60256

8zmt

EMDB-60256, PDB-8zmt:
Cryo-EM structure of Saccharomyces cerevisiae bc1 complex in Metyltetraprole-bound state
Method: EM (single particle) / Resolution: 2.52 Å

60317

8zos

EMDB-60317, PDB-8zos:
Cryo-EM structure of pyraclostrobin-bound porcine bc1 complex
Method: EM (single particle) / Resolution: 2.37 Å

60320

8zow

EMDB-60320, PDB-8zow:
Cryo-EM structure of Metyltetraprole-bound porcine bc1 complex
Method: EM (single particle) / Resolution: 2.53 Å

60323

8zp0

EMDB-60323, PDB-8zp0:
Cryo-EM structure of YF23694-bound porcine bc1 complex
Method: EM (single particle) / Resolution: 2.44 Å

Chemicals

ChemComp-6PH:
(1R)-2-(phosphonooxy)-1-[(tridecanoyloxy)methyl]ethyl pentadecanoate

ChemComp-9PE:
(1R)-2-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-1-[(heptanoyloxy)methyl]ethyl octadecanoate / phospholipid*YM

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-8PE:
(2R)-3-{[(S)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-2-(tetradecanoyloxy)propyl octadecanoate / phospholipid*YM

ChemComp-CN5:
(5S,11R)-5,8,11-trihydroxy-5,11-dioxido-17-oxo-4,6,10,12,16-pentaoxa-5,11-diphosphaoctadec-1-yl pentadecanoate

ChemComp-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

PDB-1d6k:
NMR SOLUTION STRUCTURE OF THE 5S RRNA E-LOOP/L25 COMPLEX

ChemComp-7PH:
(1R)-2-(dodecanoyloxy)-1-[(phosphonooxy)methyl]ethyl tetradecanoate

ChemComp-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

PDB-1d6o:
NATIVE FKBP

PDB-1d6p:
HUMAN LYSOZYME L63 MUTANT LABELLED WITH 2',3'-EPOXYPROPYL N,N'-DIACETYLCHITOBIOSE

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM

ChemComp-HEC:
HEME C

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM

Source
  • saccharomyces cerevisiae (brewer's yeast)
  • sus scrofa (pig)
KeywordsMEMBRANE PROTEIN / Complex / mitochondria / ELECTRON TRANSPORT / PROTEIN BINDING / Pyraclostrobin / Metyltetraprole / Inhibitor

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