3KW4

Crystal structure of cytochrome 2B4 in complex with the anti-platelet drug ticlopidine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.67 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.198 

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This is version 1.4 of the entry. See complete history


Literature

Structures of cytochrome P450 2B4 complexed with the antiplatelet drugs ticlopidine and clopidogrel.

Gay, S.C.Roberts, A.G.Maekawa, K.Talakad, J.C.Hong, W.X.Zhang, Q.Stout, C.D.Halpert, J.R.

(2010) Biochemistry 49: 8709-8720

  • DOI: https://doi.org/10.1021/bi100914z
  • Primary Citation of Related Structures:  
    3KW4, 3ME6

  • PubMed Abstract: 

    Prior X-ray crystal structures of rabbit cytochrome P450 2B4 (2B4) in complexes with various imidazoles have demonstrated markedly different enzyme conformations depending on the size of the inhibitor occupying the active site. In this study, structures of 2B4 were determined with the antiplatelet drugs clopidogrel and ticlopidine, which were expected to have greater freedom of movement in the binding pocket. Ticlopidine could be modeled into the electron density maps in two distinct orientations, both of which are consistent with metabolic data gathered with other mammalian P450 enzymes. Results of ligand docking and heme-induced NMR relaxation of drug protons showed that ticlopidine was preferentially oriented with the chlorophenyl group closest to the heme. Because of its stereocenter, clopidogrel was easier to fit in the electron density and exhibited a single orientation, which points the chlorophenyl ring toward the heme. The C(α) traces of both complexes aligned very well with each other and revealed a compact, closed structure that resembles the conformation observed in two previously determined 2B4 structures with the small molecule inhibitors 4-(4-chlorophenyl)imidazole and 1-(4-chlorophenyl)imidazole. The 2B4 active site is able to accommodate small ligands by moving only a small number of side chains, suggesting that ligand reorientation is energetically favored over protein conformational changes for binding of these similarly sized molecules. Adjusting both protein conformation and ligand orientation in the active site gives 2B4 the flexibility to bind to the widest range of molecules, while also being energetically favorable.


  • Organizational Affiliation

    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA. scgay@ucsd.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 2B4476Oryctolagus cuniculusMutation(s): 9 
Gene Names: CYP2B4
EC: 1.14.14.1
UniProt
Find proteins for P00178 (Oryctolagus cuniculus)
Explore P00178 
Go to UniProtKB:  P00178
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00178
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CH0
Query on CH0

Download Ideal Coordinates CCD File 
F [auth A]2-{[(3alpha,5alpha,7alpha,8alpha,10alpha,12alpha,17alpha)-3,12-bis{2-[(4-O-alpha-D-glucopyranosyl-beta-D-glucopyranosyl)oxy]ethoxy}cholan-7-yl]oxy}ethyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside
C66 H114 O36
YGUVIEOMNBFSRV-GLUVFYGUSA-N
HEM
Query on HEM

Download Ideal Coordinates CCD File 
B [auth A]PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
CM5
Query on CM5

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A]
5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE
C23 H42 O11
RVTGFZGNOSKUDA-ZNGNCRBCSA-N
TIC
Query on TIC

Download Ideal Coordinates CCD File 
C [auth A]ticlopidine
C14 H14 Cl N S
PHWBOXQYWZNQIN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.67 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.198 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.5α = 90
b = 93.5β = 90
c = 137.07γ = 120
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-09-15
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-08-31
    Changes: Atomic model
  • Version 1.3: 2021-10-13
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-09-06
    Changes: Data collection, Refinement description