PDBsum entry 4pd4

Oxidoreductase/inhibitor

PDB id: 4pd4

Contents

Protein chains

431 a.a.

352 a.a.

385 a.a.

248 a.a.

185 a.a.

74 a.a.

126 a.a.

93 a.a.

57 a.a.

127 a.a.

107 a.a.

Ligands

UMQ

3PH ×3

HEM ×3

AOQ

3PE

UQ6

FES

PDB id:

4pd4

Name:

Oxidoreductase/inhibitor

Title:

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

Structure:

Cytochrome b-c1 complex subunit 1, mitochondrial. Chain: a. Fragment: unp residues 27-457. 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. Fragment: unp residues 17-368. Synonym: complex iii subunit 2,core protein ii,ubiquinol-cytochromE-C

Source:

Saccharomyces cerevisiae (strain atcc 204508 / s288c). Baker's yeast. Organism_taxid: 559292. Strain: atcc 204508 / s288c. Mus musculus. Mouse. Organism_taxid: 10090. Gene: igh.

Resolution:

3.04Å R-factor: 0.269 R-free: 0.297

Authors:

D.Birth,W.-C.Kao,C.Hunte

Key ref:

D.Birth et al. (2014). Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action. Nat Commun, 5, 4029. PubMed id: 24893593 DOI: 10.1038/ncomms5029

Date:

17-Apr-14 Release date: 11-Jun-14

Protein chain

P07256  (QCR1_YEAST) -  Cytochrome b-c1 complex subunit 1, mitochondrial from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 457 a.a.

Struc: 431 a.a.*

Protein chain

P07257  (QCR2_YEAST) -  Cytochrome b-c1 complex subunit 2, mitochondrial from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 368 a.a.

Struc: 352 a.a.

Protein chain

P00163  (CYB_YEAST) -  Cytochrome b from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 385 a.a.

Struc: 385 a.a.

Protein chain

P07143  (CY1_YEAST) -  Cytochrome c1, heme protein, mitochondrial from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 309 a.a.

Struc: 248 a.a.

Protein chain

P08067  (UCRI_YEAST) -  Cytochrome b-c1 complex subunit Rieske, mitochondrial from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 215 a.a.

Struc: 185 a.a.

Protein chain

P00127  (QCR6_YEAST) -  Cytochrome b-c1 complex subunit 6, mitochondrial from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 147 a.a.

Struc: 74 a.a.

Protein chain

P00128  (QCR7_YEAST) -  Cytochrome b-c1 complex subunit 7, mitochondrial from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 127 a.a.

Struc: 126 a.a.

Protein chain

P08525  (QCR8_YEAST) -  Cytochrome b-c1 complex subunit 8, mitochondrial from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 94 a.a.

Struc: 93 a.a.

Protein chain

P22289  (QCR9_YEAST) -  Cytochrome b-c1 complex subunit 9, mitochondrial from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 66 a.a.

Struc: 57 a.a.

Protein chain

Q53VQ5  (Q53VQ5_MOUSE) -  Ig-like domain-containing protein (Fragment) from Mus musculus

Seq: 119 a.a.

Struc: 127 a.a.*

Protein chain

P01647  (KV5AE_MOUSE) -  Ig kappa chain V-V region HP 124E1 from Mus musculus

Seq: 108 a.a.

Struc: 107 a.a.*

* PDB and UniProt seqs differ at 36 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains C, D, E: 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)

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

Key reference

DOI no: 10.1038/ncomms5029

Nat Commun 5:4029 (2014)

PubMed id: 24893593

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action.

D.Birth, W.C.Kao, C.Hunte.

ABSTRACT

Atovaquone, a substituted hydroxynaphthoquinone, is a potent antimalarial drug that acts by inhibiting the parasite's mitochondrial cytochrome bc1 complex (cyt bc1). Mutations in cyt bc1 confer atovaquone resistance. Here we describe the X-ray structure of mitochondrial cyt bc1 from Saccharomyces cerevisiae with atovaquone bound in the catalytic Qo site, at 3.0-Å resolution. A polarized H-bond to His181 of the Rieske protein in cyt bc1 traps the ionized hydroxyl group of the drug. Side chains of highly conserved cytochrome b residues establish multiple non-polar interactions with the napththoquinone group, whereas less-conserved residues are in contact with atovaquone's cyclohexyl-chlorophenyl tail. Our structural analysis reveals the molecular basis of atovaquone's broad target spectrum, species-specific efficacies and acquired resistances, and may aid drug development to control the spread of resistant parasites.