3TGU

Cytochrome bc1 complex from chicken with pfvs-designed moa inhibitor bound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.258 
  • R-Value Observed: 0.258 

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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex.

Hao, G.F.Wang, F.Li, H.Zhu, X.L.Yang, W.C.Huang, L.S.Wu, J.W.Berry, E.A.Yang, G.F.

(2012) J Am Chem Soc 134: 11168-11176

  • DOI: https://doi.org/10.1021/ja3001908
  • Primary Citation of Related Structures:  
    3TGU

  • PubMed Abstract: 

    A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q(o) site inhibitors of the cytochrome bc(1) complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K(i) = 881.80 nM, porcine bc(1)), the most potent compound 4f displayed 20 507-fold improved binding affinity (K(i) = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K(i) = 83.00 pM) bound to the chicken bc(1) at 2.70 Å resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques.


  • Organizational Affiliation

    Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitochondrial ubiquinol-cytochrome-c reductase complex core protein iA,
K [auth N]
446Gallus gallusMutation(s): 0 
EC: 1.10.2.2
UniProt
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Mitochondrial ubiquinol-cytochrome-c reductase complex core protein 2B,
L [auth O]
441Gallus gallusMutation(s): 0 
EC: 1.10.2.2
UniProt
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome bC,
M [auth P]
380Gallus gallusMutation(s): 0 
Membrane Entity: Yes 
UniProt
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Mitochondrial cytochrome c1, heme proteinD,
N [auth Q]
241Gallus gallusMutation(s): 0 
EC: 1.10.2.2
Membrane Entity: Yes 
UniProt
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit Rieske, mitochondrialE,
O [auth R]
196Gallus gallusMutation(s): 0 
EC: 1.10.2.2
Membrane Entity: Yes 
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Mitochondrial ubiquinol-cytochrome c reductase 14 kda proteinF,
P [auth S]
110Gallus gallusMutation(s): 0 
EC: 1.10.2.2
Membrane Entity: Yes 
UniProt
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Mitochondrial ubiquinol-cytochrome c reductase ubiquinone-binding protein qp-cG,
Q [auth T]
81Gallus gallusMutation(s): 0 
EC: 1.10.2.2
Membrane Entity: Yes 
UniProt
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Mitochondrial ubiquinol-cytochrome c reductase 11 kda protein, complex iii subunit viiiH,
R [auth U]
77Gallus gallusMutation(s): 0 
EC: 1.10.2.2
Membrane Entity: Yes 
UniProt
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit Rieske, mitochondrialI,
S [auth V]
76Gallus gallusMutation(s): 0 
EC: 1.10.2.2
Membrane Entity: Yes 
UniProt
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Mitochondrial ubiquinol-cytochrome c reductase 7.2 kda proteinJ,
T [auth W]
61Gallus gallusMutation(s): 0 
EC: 1.10.2.2
Membrane Entity: Yes 
UniProt
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Small Molecules
Ligands 10 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CDL
Query on CDL

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IA [auth G],
QA [auth P],
UA [auth Q],
Z [auth C]
CARDIOLIPIN
C81 H156 O17 P2
XVTUQDWPJJBEHJ-KZCWQMDCSA-L
UQ
Query on UQ

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PA [auth P],
Y [auth C]
Coenzyme Q10, (2Z,6E,10Z,14E,18E,22E,26Z)-isomer
C59 H90 O4
ACTIUHUUMQJHFO-RECDIHICSA-N
PEE
Query on PEE

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AA [auth C]
BA [auth C]
HA [auth E]
KA [auth N]
RA [auth P]
AA [auth C],
BA [auth C],
HA [auth E],
KA [auth N],
RA [auth P],
YA [auth R]
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
C41 H78 N O8 P
MWRBNPKJOOWZPW-NYVOMTAGSA-N
HEC
Query on HEC

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DA [auth D],
TA [auth Q]
HEME C
C34 H34 Fe N4 O4
HXQIYSLZKNYNMH-LJNAALQVSA-N
HEM
Query on HEM

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LA [auth P],
MA [auth P],
V [auth C],
W [auth C]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
WF3
Query on WF3

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OA [auth P],
X [auth C]
methyl (2E)-3-methoxy-2-[2-({[6-methyl-3-(trifluoromethyl)quinoxalin-2-yl]oxy}methyl)phenyl]prop-2-enoate
C22 H19 F3 N2 O4
GJLNLJPTCNQCFH-FOWTUZBSSA-N
BOG
Query on BOG

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EA [auth D],
FA [auth D],
NA [auth P],
VA [auth Q],
WA [auth Q]
octyl beta-D-glucopyranoside
C14 H28 O6
HEGSGKPQLMEBJL-RKQHYHRCSA-N
FES
Query on FES

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GA [auth E],
XA [auth R]
FE2/S2 (INORGANIC) CLUSTER
Fe2 S2
NIXDOXVAJZFRNF-UHFFFAOYSA-N
GOL
Query on GOL

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CA [auth C],
SA [auth P]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
UNL
Query on UNL

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JA [auth N],
U [auth A]
Unknown ligand
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
FME
Query on FME
C,
M [auth P]
L-PEPTIDE LINKINGC6 H11 N O3 SMET
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.258 
  • R-Value Observed: 0.258 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 172.678α = 90
b = 183.305β = 90
c = 241.944γ = 90
Software Package:
Software NamePurpose
Adxvdata processing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-07-04
    Type: Initial release
  • Version 1.1: 2012-10-03
    Changes: Database references
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Database references, Derived calculations, Structure summary
  • Version 2.0: 2023-09-13
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Polymer sequence, Refinement description, Structure summary