6HAW

Crystal structure of bovine cytochrome bc1 in complex with 2-pyrazolyl quinolone inhibitor WDH2G7

PDB DOI: https://doi.org/10.2210/pdb6HAW/pdb

Classification: ELECTRON TRANSPORT
Organism(s): Bos taurus
Mutation(s): No
Membrane Protein: Yes PDBTMMemProtMD

Deposited: 2018-08-08 Released: 2019-01-16
Deposition Author(s): Amporndanai, K., Hong, W.D., O'Neill, P.M., Hasnain, S.S., Antonyuk, S.V.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.45 ?
R-Value Free: 0.242
R-Value Work: 0.210
R-Value Observed: 0.212

Starting Model: experimental
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Ligand Structure Quality Assessment

This is version 2.0 of the entry. See complete history.

Literature

Potent Antimalarial 2-Pyrazolyl Quinolonebc1(Qi) Inhibitors with Improved Drug-like Properties.

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

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

PubMed: 30613327 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.8b00371
Primary Citation of Related Structures:
6HAW

PubMed 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 IC ₅₀ (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 bc ₁ complex, which is supported by crystallographic studies of bovine cytochrome bc ₁ complex.

Organizational Affiliation

Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K.

Macromolecule Content

Total Structure Weight: 238.53 kDa
Atom Count: 16,062
Modelled Residue Count: 2,006
Deposited Residue Count: 2,006
Unique protein chains: 10

Macromolecules

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Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome b-c1 complex subunit 1, mitochondrial	A	438	Bos taurus	Mutation(s): 0 Membrane Entity: Yes
UniProt
Find proteins for P31800 (Bos taurus) Explore P31800 Go to UniProtKB: P31800
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P31800
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Reference Sequence

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Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome b-c1 complex subunit 2, mitochondrial	B	413	Bos taurus	Mutation(s): 0 Membrane Entity: Yes
UniProt
Find proteins for P23004 (Bos taurus) Explore P23004 Go to UniProtKB: P23004
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P23004
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Reference Sequence

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Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome b	C	378	Bos taurus	Mutation(s): 0 Membrane Entity: Yes
UniProt
Find proteins for P00157 (Bos taurus) Explore P00157 Go to UniProtKB: P00157
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00157
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Reference Sequence

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Entity ID: 4
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome c1, heme protein, mitochondrial	D	239	Bos taurus	Mutation(s): 0 EC: 7.1.1.8 Membrane Entity: Yes
UniProt
Find proteins for P00125 (Bos taurus) Explore P00125 Go to UniProtKB: P00125
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00125
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Reference Sequence

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Entity ID: 5
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome b-c1 complex subunit Rieske, mitochondrial	E	196	Bos taurus	Mutation(s): 0 EC: 1.10.2.2 (PDB Primary Data), 7.1.1.8 (UniProt) Membrane Entity: Yes
UniProt
Find proteins for P13272 (Bos taurus) Explore P13272 Go to UniProtKB: P13272
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P13272
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Reference Sequence

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Entity ID: 6
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome b-c1 complex subunit 7	F	99	Bos taurus	Mutation(s): 0 Membrane Entity: Yes
UniProt
Find proteins for P00129 (Bos taurus) Explore P00129 Go to UniProtKB: P00129
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UniProt Group	P00129
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Reference Sequence

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Entity ID: 7
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome b-c1 complex subunit 8	G	74	Bos taurus	Mutation(s): 0 Membrane Entity: Yes
UniProt
Find proteins for P13271 (Bos taurus) Explore P13271 Go to UniProtKB: P13271
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P13271
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Reference Sequence

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Entity ID: 8
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome b-c1 complex subunit 6, mitochondrial	H	64	Bos taurus	Mutation(s): 0 Membrane Entity: Yes
UniProt
Find proteins for P00126 (Bos taurus) Explore P00126 Go to UniProtKB: P00126
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00126
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Reference Sequence

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Entity ID: 9
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome b-c1 complex subunit Rieske, mitochondrial	I	46	Bos taurus	Mutation(s): 0 EC: 1.10.2.2 (PDB Primary Data), 7.1.1.8 (UniProt) Membrane Entity: Yes
UniProt
Find proteins for P13272 (Bos taurus) Explore P13272 Go to UniProtKB: P13272
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P13272
Sequence Annotations Expand
Reference Sequence

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Entity ID: 10
Molecule	Chains	Sequence Length	Organism	Details	Image
Cytochrome b-c1 complex subunit 9	J	59	Bos taurus	Mutation(s): 0 Membrane Entity: Yes
UniProt
Find proteins for P00130 (Bos taurus) Explore P00130 Go to UniProtKB: P00130
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00130
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 13 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
CDL Query on CDL Download Ideal Coordinates CCD File SDF format, chain FA [auth D] SDF format, chain KA [auth E] SDF format, chain P [auth A] SDF format, chain W [auth C] MOL2 format, chain FA [auth D] MOL2 format, chain KA [auth E] MOL2 format, chain P [auth A] MOL2 format, chain W [auth C] mmCIF format, chain FA [auth D] mmCIF format, chain KA [auth E] mmCIF format, chain P [auth A] mmCIF format, chain W [auth C]	FA [auth D], KA [auth E], P [auth A], W [auth C]	CARDIOLIPIN C₈₁ H₁₅₆ O₁₇ P₂ XVTUQDWPJJBEHJ-KZCWQMDCSA-L		Interactions Focus chain FA [auth D] Focus chain KA [auth E] Focus chain P [auth A] Focus chain W [auth C] Interactions & Density Focus chain FA [auth D] Focus chain KA [auth E] Focus chain P [auth A] Focus chain W [auth C]
PEE Query on PEE Download Ideal Coordinates CCD File SDF format, chain JA [auth E] SDF format, chain X [auth C] MOL2 format, chain JA [auth E] MOL2 format, chain X [auth C] mmCIF format, chain JA [auth E] mmCIF format, chain X [auth C]	JA [auth E], X [auth C]	1,2-dioleoyl-sn-glycero-3-phosphoethanolamine C₄₁ H₇₈ N O₈ P MWRBNPKJOOWZPW-NYVOMTAGSA-N		Interactions Focus chain JA [auth E] Focus chain X [auth C] Interactions & Density Focus chain JA [auth E] Focus chain X [auth C]
PX4 Query on PX4 Download Ideal Coordinates CCD File SDF format, chain HA [auth E] MOL2 format, chain HA [auth E] mmCIF format, chain HA [auth E]	HA [auth E]	1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE C₃₆ H₇₃ N O₈ P CITHEXJVPOWHKC-UUWRZZSWSA-O		Interactions Focus chain HA [auth E] Interactions & Density Focus chain HA [auth E]
PX6 Query on PX6 Download Ideal Coordinates CCD File SDF format, chain CA [auth C] SDF format, chain S [auth B] MOL2 format, chain CA [auth C] MOL2 format, chain S [auth B] mmCIF format, chain CA [auth C] mmCIF format, chain S [auth B]	CA [auth C], S [auth B]	1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHATE C₃₅ H₆₈ O₈ P PORPENFLTBBHSG-MGBGTMOVSA-M		Interactions Focus chain CA [auth C] Focus chain S [auth B] Interactions & Density Focus chain CA [auth C] Focus chain S [auth B]
HEC Query on HEC Download Ideal Coordinates CCD File SDF format, chain DA [auth D] MOL2 format, chain DA [auth D] mmCIF format, chain DA [auth D]	DA [auth D]	HEME C C₃₄ H₃₄ Fe N₄ O₄ HXQIYSLZKNYNMH-LJNAALQVSA-N		Interactions Focus chain DA [auth D] Interactions & Density Focus chain DA [auth D]
HEM Query on HEM Download Ideal Coordinates CCD File SDF format, chain T [auth C] SDF format, chain U [auth C] MOL2 format, chain T [auth C] MOL2 format, chain U [auth C] mmCIF format, chain T [auth C] mmCIF format, chain U [auth C]	T [auth C], U [auth C]	PROTOPORPHYRIN IX CONTAINING FE C₃₄ H₃₂ Fe N₄ O₄ KABFMIBPWCXCRK-RGGAHWMASA-L		Interactions Focus chain T [auth C] Focus chain U [auth C] Interactions & Density Focus chain T [auth C] Focus chain U [auth C]
LMT Query on LMT Download Ideal Coordinates CCD File SDF format, chain V [auth C] MOL2 format, chain V [auth C] mmCIF format, chain V [auth C]	V [auth C]	DODECYL-BETA-D-MALTOSIDE C₂₄ H₄₆ O₁₁ NLEBIOOXCVAHBD-QKMCSOCLSA-N		Interactions Focus chain V [auth C] Interactions & Density Focus chain V [auth C]
FX2 (Subject of Investigation/LOI) Query on FX2 Download Ideal Coordinates CCD File SDF format, chain Y [auth C] MOL2 format, chain Y [auth C] mmCIF format, chain Y [auth C]	Y [auth C]	7-methoxy-3-methyl-2-[1-[[4-(trifluoromethyloxy)phenyl]methyl]pyrazol-4-yl]-3~{H}-quinolin-4-one C₂₂ H₁₈ F₃ N₃ O₃ MHUJCWZTTGWJRK-ZDUSSCGKSA-N		Interactions Focus chain Y [auth C] Interactions & Density Focus chain Y [auth C]
6PE Query on 6PE Download Ideal Coordinates CCD File SDF format, chain K [auth A] MOL2 format, chain K [auth A] mmCIF format, chain K [auth A]	K [auth A]	1,2-DIHEXANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE C₁₇ H₃₃ N O₈ P PELYUHWUVHDSSU-OAHLLOKOSA-M		Interactions Focus chain K [auth A] Interactions & Density Focus chain K [auth A]
PG4 Query on PG4 Download Ideal Coordinates CCD File SDF format, chain R [auth B] MOL2 format, chain R [auth B] mmCIF format, chain R [auth B]	R [auth B]	TETRAETHYLENE GLYCOL C₈ H₁₈ O₅ UWHCKJMYHZGTIT-UHFFFAOYSA-N		Interactions Focus chain R [auth B] Interactions & Density Focus chain R [auth B]
FES Query on FES Download Ideal Coordinates CCD File SDF format, chain GA [auth E] MOL2 format, chain GA [auth E] mmCIF format, chain GA [auth E]	GA [auth E]	FE2/S2 (INORGANIC) CLUSTER Fe₂ S₂ NIXDOXVAJZFRNF-UHFFFAOYSA-N		Interactions Focus chain GA [auth E] Interactions & Density Focus chain GA [auth E]
PGE Query on PGE Download Ideal Coordinates CCD File SDF format, chain AA [auth C] SDF format, chain BA [auth C] SDF format, chain L [auth A] SDF format, chain Z [auth C] MOL2 format, chain AA [auth C] MOL2 format, chain BA [auth C] MOL2 format, chain L [auth A] MOL2 format, chain Z [auth C] mmCIF format, chain AA [auth C] mmCIF format, chain BA [auth C] mmCIF format, chain L [auth A] mmCIF format, chain Z [auth C]	AA [auth C], BA [auth C], L [auth A], Z [auth C]	TRIETHYLENE GLYCOL C₆ H₁₄ O₄ ZIBGPFATKBEMQZ-UHFFFAOYSA-N		Interactions Focus chain AA [auth C] Focus chain BA [auth C] Focus chain L [auth A] Focus chain Z [auth C] Interactions & Density Focus chain AA [auth C] Focus chain BA [auth C] Focus chain L [auth A] Focus chain Z [auth C]
PO4 Query on PO4 Download Ideal Coordinates CCD File SDF format, chain EA [auth D] SDF format, chain IA [auth E] SDF format, chain LA [auth F] SDF format, chain M [auth A] SDF format, chain MA [auth F] SDF format, chain NA [auth G] SDF format, chain O [auth A] SDF format, chain PA [auth G] SDF format, chain Q [auth B] SDF format, chain N [auth A] SDF format, chain OA [auth G] MOL2 format, chain EA [auth D] MOL2 format, chain IA [auth E] MOL2 format, chain LA [auth F] MOL2 format, chain M [auth A] MOL2 format, chain MA [auth F] MOL2 format, chain NA [auth G] MOL2 format, chain O [auth A] MOL2 format, chain PA [auth G] MOL2 format, chain Q [auth B] MOL2 format, chain N [auth A] MOL2 format, chain OA [auth G] mmCIF format, chain EA [auth D] mmCIF format, chain IA [auth E] mmCIF format, chain LA [auth F] mmCIF format, chain M [auth A] mmCIF format, chain MA [auth F] mmCIF format, chain NA [auth G] mmCIF format, chain O [auth A] mmCIF format, chain PA [auth G] mmCIF format, chain Q [auth B] mmCIF format, chain N [auth A] mmCIF format, chain OA [auth G]	EA [auth D] IA [auth E] LA [auth F] M [auth A] MA [auth F] EA [auth D], IA [auth E], LA [auth F], M [auth A], MA [auth F], N [auth A], NA [auth G], O [auth A], OA [auth G], PA [auth G], Q [auth B]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain EA [auth D] Focus chain IA [auth E] Focus chain LA [auth F] Focus chain M [auth A] Focus chain MA [auth F] Focus chain N [auth A] Focus chain NA [auth G] Focus chain O [auth A] Focus chain OA [auth G] Focus chain PA [auth G] Focus chain Q [auth B] Interactions & Density Focus chain EA [auth D] Focus chain IA [auth E] Focus chain LA [auth F] Focus chain M [auth A] Focus chain MA [auth F] Focus chain N [auth A] Focus chain NA [auth G] Focus chain O [auth A] Focus chain OA [auth G] Focus chain PA [auth G] Focus chain Q [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 3.45 ?
R-Value Free: 0.242
R-Value Work: 0.210
R-Value Observed: 0.212
Space Group: P 6₅ 2 2

Unit Cell:

Length ( ? )	Angle ( ? )
a = 212.69	α = 90
b = 212.69	β = 90
c = 347.066	γ = 120

Software Package:

Software Name	Purpose
MOSFLM	data reduction
Aimless	data scaling
REFMAC	refinement
PDB_EXTRACT	data extraction

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2019-01-16

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2019-01-16
Type: Initial release
Version 2.0: 2024-01-17
Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Refinement description, Structure summary

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Help and Resources

6HAW

Crystal structure of bovine cytochrome bc1 in complex with 2-pyrazolyl quinolone inhibitor WDH2G7

Potent Antimalarial 2-Pyrazolyl Quinolonebc1(Qi) Inhibitors with Improved Drug-like Properties.

Entity ID: 1

UniProt

Entity Groups

Sequence Annotations

Entity ID: 2

UniProt

Entity Groups

Sequence Annotations

Entity ID: 3

UniProt

Entity Groups

Sequence Annotations

Entity ID: 4

UniProt

Entity Groups

Sequence Annotations

Entity ID: 5

UniProt

Entity Groups

Sequence Annotations

Entity ID: 6

UniProt

Entity Groups

Sequence Annotations

Entity ID: 7

UniProt

Entity Groups

Sequence Annotations

Entity ID: 8

UniProt

Entity Groups

Sequence Annotations

Entity ID: 9

UniProt

Entity Groups

Sequence Annotations

Entity ID: 10

UniProt

Entity Groups

Sequence Annotations

Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)