2F9Q

Crystal Structure of Human Cytochrome P450 2D6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.232 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Crystal Structure of Human Cytochrome P450 2D6

Rowland, P.Blaney, F.E.Smyth, M.G.Jones, J.J.Leydon, V.R.Oxbrow, A.K.Lewis, C.J.Tennant, M.G.Modi, S.Eggleston, D.S.Chenery, R.J.Bridges, A.M.

(2006) J Biol Chem 281: 7614-7622

  • DOI: https://doi.org/10.1074/jbc.M511232200
  • Primary Citation of Related Structures:  
    2F9Q

  • PubMed Abstract: 

    Cytochrome P450 2D6 is a heme-containing enzyme that is responsible for the metabolism of at least 20% of known drugs. Substrates of 2D6 typically contain a basic nitrogen and a planar aromatic ring. The crystal structure of human 2D6 has been solved and refined to 3.0A resolution. The structure shows the characteristic P450 fold as seen in other members of the family, with the lengths and orientations of the individual secondary structural elements being very similar to those seen in 2C9. There are, however, several important differences, the most notable involving the F helix, the F-G loop, the B'helix, beta sheet 4, and part of beta sheet 1, all of which are situated on the distal face of the protein. The 2D6 structure has a well defined active site cavity above the heme group, containing many important residues that have been implicated in substrate recognition and binding, including Asp-301, Glu-216, Phe-483, and Phe-120. The crystal structure helps to explain how Asp-301, Glu-216, and Phe-483 can act as substrate binding residues and suggests that the role of Phe-120 is to control the orientation of the aromatic ring found in most substrates with respect to the heme. The structure has been compared with published homology models and has been used to explain much of the reported site-directed mutagenesis data and help understand the metabolism of several compounds.


  • Organizational Affiliation

    Department of Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom. Paul_2_Rowland@gsk.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 2D6
A, B, C, D
479Homo sapiensMutation(s): 2 
Gene Names: CYP2D6
EC: 1.14.14.1
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P10635 (Homo sapiens)
Explore P10635 
Go to UniProtKB:  P10635
PHAROS:  P10635
GTEx:  ENSG00000100197 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP10635
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.232 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 145.066α = 90
b = 155.495β = 90
c = 95.801γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2005-12-20 
  • Deposition Author(s): Rowland, P.

Revision History  (Full details and data files)

  • Version 1.0: 2005-12-20
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Refinement description, Version format compliance
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2024-02-14
    Changes: Data collection, Refinement description