PDBsum entry 4d6t

Electron transport

PDB id: 4d6t

Contents

Protein chains

444 a.a.

422 a.a.

374 a.a.

240 a.a.

73 a.a.

98 a.a.

80 a.a.

65 a.a.

21 a.a.

58 a.a.

196 a.a.

74 a.a.

17 a.a.

59 a.a.

Ligands

HEM ×4

4X9 ×2

PO4 ×11

PEE ×4

HEC ×2

CDL ×4

FES

GOL

PDB id:

4d6t

Name:

Electron transport

Title:

Cytochrome bc1 bound to the 4(1h)-pyridone gw844520

Structure:

Cytochrome b-c1 complex subunit 1, mitochondrial. Chain: a, n. Synonym: complex iii subunit 1, core protein i, ubiquinol-cytochrome -c reductase complex core protein 1. Cytochrome b-c1 complex subunit 2, mitochondrial. Chain: b. Synonym: complex iii subunit 2, core protein ii, ubiquinol- cytochromE-C reductase complex core protein 2. Cytochrome b.

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Organ: heart. Tissue: muscle. Tissue: muscle

Resolution:

3.57Å R-factor: 0.208 R-free: 0.252

Authors:

M.J.Capper,P.M.O'Neill,N.Fisher,R.W.Strange,D.Moss,S.A.Ward, N.G.Berry,A.S.Lawrenson,S.S.Hasnain,G.A.Biagini,S.V.Antonyuk

Key ref:

M.J.Capper et al. (2015). Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1. Proc Natl Acad Sci U S A, 112, 755-760. PubMed id: 25564664 DOI: 10.1073/pnas.1416611112

Date:

14-Nov-14 Release date: 14-Jan-15

Protein chains

P31800  (QCR1_BOVIN) -  Cytochrome b-c1 complex subunit 1, mitochondrial from Bos taurus

Seq: 480 a.a.

Struc: 444 a.a.

Protein chains

P23004  (QCR2_BOVIN) -  Cytochrome b-c1 complex subunit 2, mitochondrial from Bos taurus

Seq: 453 a.a.

Struc: 422 a.a.

Protein chains

P00157  (CYB_BOVIN) -  Cytochrome b from Bos taurus

Seq: 379 a.a.

Struc: 374 a.a.

Protein chains

P00125  (CY1_BOVIN) -  Cytochrome c1, heme protein, mitochondrial from Bos taurus

Seq: 325 a.a.

Struc: 240 a.a.

Protein chain

P13272  (UCRI_BOVIN) -  Cytochrome b-c1 complex subunit Rieske, mitochondrial from Bos taurus

Seq: 274 a.a.

Struc: 73 a.a.

Protein chains

P00129  (QCR7_BOVIN) -  Cytochrome b-c1 complex subunit 7 from Bos taurus

Seq: 111 a.a.

Struc: 98 a.a.*

Protein chain

P13271  (QCR8_BOVIN) -  Cytochrome b-c1 complex subunit 8 from Bos taurus

Seq: 82 a.a.

Struc: 80 a.a.

Protein chains

P00126  (QCR6_BOVIN) -  Cytochrome b-c1 complex subunit 6, mitochondrial from Bos taurus

Seq: 91 a.a.

Struc: 65 a.a.

Protein chain

P13272  (UCRI_BOVIN) -  Cytochrome b-c1 complex subunit Rieske, mitochondrial from Bos taurus

Seq: 274 a.a.

Struc: 21 a.a.

Protein chain

P00130  (QCR9_BOVIN) -  Cytochrome b-c1 complex subunit 9 from Bos taurus

Seq: 64 a.a.

Struc: 58 a.a.

Protein chain

P13272  (UCRI_BOVIN) -  Cytochrome b-c1 complex subunit Rieske, mitochondrial from Bos taurus

Seq: 274 a.a.

Struc: 196 a.a.

Protein chain

P13271  (QCR8_BOVIN) -  Cytochrome b-c1 complex subunit 8 from Bos taurus

Seq: 82 a.a.

Struc: 74 a.a.

Protein chain

P13272  (UCRI_BOVIN) -  Cytochrome b-c1 complex subunit Rieske, mitochondrial from Bos taurus

Seq: 274 a.a.

Struc: 17 a.a.*

Protein chain

P00130  (QCR9_BOVIN) -  Cytochrome b-c1 complex subunit 9 from Bos taurus

Seq: 64 a.a.

Struc: 59 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains D, E, I, Q, R, V: E.C.7.1.1.8 - quinol--cytochrome-c reductase.
• Reaction: a quinol + 2 Fe(III)-[cytochrome c](out) = a quinone + 2 Fe(II)- [cytochrome c](out) + 2 H(+)(out)

quinol + 2 × Fe(III)-[cytochrome c](out) = quinone (Bound ligand (Het Group name = GOL) matches with 40.00% similarity) + 2 × Fe(II)- [cytochrome c](out) + 2 × H(+)(out)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

DOI no: 10.1073/pnas.1416611112

Proc Natl Acad Sci U S A 112:755-760 (2015)

PubMed id: 25564664

Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1.

M.J.Capper, P.M.O'Neill, N.Fisher, R.W.Strange, D.Moss, S.A.Ward, N.G.Berry, A.S.Lawrenson, S.S.Hasnain, G.A.Biagini, S.V.Antonyuk.

ABSTRACT

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.