PDBsum entry 6haw

Electron transport

PDB id: 6haw

Contents

Protein chains

438 a.a.

413 a.a.

378 a.a.

239 a.a.

196 a.a.

99 a.a.

74 a.a.

64 a.a.

46 a.a.

59 a.a.

Ligands

6PE

PGE ×4

PO4 ×11

CDL ×4

PG4

PX6 ×2

HEM ×2

LMT

PEE ×2

FX2

HEC

FES

PX4

Waters ×30

PDB id:

6haw

Name:

Electron transport

Title:

Crystal structure of bovine cytochrome bc1 in complex with 2-pyrazolyl quinolone inhibitor wdh2g7

Structure:

Cytochrome b-c1 complex subunit 1, mitochondrial. Chain: a. 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. Cytochrome b. Chain: c. Synonym: complex iii subunit 3,complex iii subunit iii,cytochrome b-

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Organism_taxid: 9913

Resolution:

3.45Å R-factor: 0.212 R-free: 0.242

Authors:

K.Amporndanai,W.D.Hong,P.M.O'Neill,S.S.Hasnain,S.V.Antonyuk

Key ref:

W.David Hong et al. (2018). Potent Antimalarial 2-Pyrazolyl Quinolone bc₁ (Q_i) Inhibitors with Improved Drug-like Properties. ACS Med Chem Lett, 9, 1205-1210. PubMed id: 30613327 DOI: 10.1021/acsmedchemlett.8b00371

Date:

08-Aug-18 Release date: 16-Jan-19

Protein chain

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

Seq: 480 a.a.

Struc: 438 a.a.

Protein chain

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

Seq: 453 a.a.

Struc: 413 a.a.

Protein chain

P00157  (CYB_BOVIN) -  Cytochrome b from Bos taurus

Seq: 379 a.a.

Struc: 378 a.a.

Protein chain

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

Seq: 325 a.a.

Struc: 239 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

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

Seq: 111 a.a.

Struc: 99 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

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

Seq: 91 a.a.

Struc: 64 a.a.

Protein chain

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

Seq: 274 a.a.

Struc: 46 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 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: Chains A, B, C, F, G, H, J: E.C.?
• Enzyme class 3: Chains D, E, I: 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)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

Key reference

DOI no: 10.1021/acsmedchemlett.8b00371

ACS Med Chem Lett 9:1205-1210 (2018)

PubMed id: 30613327

Potent Antimalarial 2-Pyrazolyl Quinolone bc₁ (Q_i) Inhibitors with Improved Drug-like Properties.

W.David Hong, S.C.Leung, K.Amporndanai, J.Davies, R.S.Priestley, G.L.Nixon, N.G.Berry, S.Samar Hasnain, S.Antonyuk, S.A.Ward, G.A.Biagini, P.M.O'Neill.

ABSTRACT

A series of 2-pyrazolyl quinolones has been designed and synthesized in 5-7 steps to optimize for both in vitro antimalarial potency and various in vitro drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC₅₀ (concentration of drug required to achieve half maximal growth suppression) values in the range of 15-33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptable safety margin through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Q_i site of the parasite bc₁ complex, which is supported by crystallographic studies of bovine cytochrome bc₁ complex.