1NR6

MICROSOMAL CYTOCHROME P450 2C5/3LVDH COMPLEX WITH DICLOFENAC


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.231 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structure of Mammalian Cytochrome P450 2C5 Complexed with Diclofenac at 2.1 A Resolution: Evidence for an Induced Fit Model of Substrate Binding

WESTER, M.R.JOHNSON, E.F.Marques-Soares, C.Dijols, S.Dansette, P.M.Mansuy, D.STOUT, C.D.

(2003) Biochemistry 42: 9335-9345

  • DOI: https://doi.org/10.1021/bi034556l
  • Primary Citation of Related Structures:  
    1NR6

  • PubMed Abstract: 

    The structure of the anti-inflammatory drug diclofenac bound in the active site of rabbit microsomal cytochrome P450 2C5/3LVdH was determined by X-ray crystallography to 2.1 A resolution. P450 2C5/3LVdH and the related enzyme 2C5dH catalyze the 4'-hydroxylation of diclofenac with apparent K(m) values of 80 and 57 microM and k(cat) values of 13 and 16 min(-1), respectively. Spectrally determined binding constants are similar to the K(m) values. The structure indicates that the pi-electron system of the dichlorophenyl moiety faces the heme Fe with the 3'- and 4'-carbons located 4.4 and 4.7 A, respectively, from the Fe. The carboxyl moiety of the substrate is hydrogen bonded to a cluster of waters that are also hydrogen bonded to the side chains of N204, K241, S289, and D290 as well as the backbone of the protein. The proximity of the diclofenac carboxylate to the side chain of D290 together with an increased binding affinity at lower pH suggests that diclofenac is protonated when bound to the enzyme. The structure exhibits conformational changes indicative of an adaptive fit to the substrate reflecting both the hydration and size of the substrate. These results indicate how structurally diverse substrates are recognized by drug-metabolizing P450 enzymes.


  • Organizational Affiliation

    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM-255, La Jolla, California 92037, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CYTOCHROME P450 2C5473Oryctolagus cuniculusMutation(s): 13 
Gene Names: CYP2C5
EC: 1.14.14.1
Membrane Entity: Yes 
UniProt
Find proteins for P00179 (Oryctolagus cuniculus)
Explore P00179 
Go to UniProtKB:  P00179
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00179
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

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

Download Ideal Coordinates CCD File 
E [auth A]2-[2,6-DICHLOROPHENYL)AMINO]BENZENEACETIC ACID
C14 H11 Cl2 N O2
DCOPUUMXTXDBNB-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
DIF Binding MOAD:  1NR6 Kd: 5.00e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.231 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.94α = 90
b = 130.02β = 90
c = 172.78γ = 90
Software Package:
Software NamePurpose
SSRLdata collection
MOSFLMdata reduction
CCP4data reduction
CNSrefinement
Blu-Icedata collection
CCP4data scaling
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-08-12
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-16
    Changes: Data collection, Refinement description