2HI4

Crystal Structure of Human Microsomal P450 1A2 in complex with alpha-naphthoflavone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.223 

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This is version 1.4 of the entry. See complete history


Literature

Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2.

Sansen, S.Yano, J.K.Reynald, R.L.Schoch, G.A.Griffin, K.J.Stout, C.D.Johnson, E.F.

(2007) J Biol Chem 282: 14348-14355

  • DOI: https://doi.org/10.1074/jbc.M611692200
  • Primary Citation of Related Structures:  
    2HI4

  • PubMed Abstract: 

    Microsomal cytochrome P450 family 1 enzymes play prominent roles in xenobiotic detoxication and procarcinogen activation. P450 1A2 is the principal cytochrome P450 family 1 enzyme expressed in human liver and participates extensively in drug oxidations. This enzyme is also of great importance in the bioactivation of mutagens, including the N-hydroxylation of arylamines. P450-catalyzed reactions involve a wide range of substrates, and this versatility is reflected in a structural diversity evident in the active sites of available P450 structures. Here, we present the structure of human P450 1A2 in complex with the inhibitor alpha-naphthoflavone, determined to a resolution of 1.95 A. alpha-Naphthoflavone is bound in the active site above the distal surface of the heme prosthetic group. The structure reveals a compact, closed active site cavity that is highly adapted for the positioning and oxidation of relatively large, planar substrates. This unique topology is clearly distinct from known active site architectures of P450 family 2 and 3 enzymes and demonstrates how P450 family 1 enzymes have evolved to catalyze efficiently polycyclic aromatic hydrocarbon oxidation. This report provides the first structure of a microsomal P450 from family 1 and offers a template to study further structure-function relationships of alternative substrates and other cytochrome P450 family 1 members.


  • Organizational Affiliation

    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 1A2495Homo sapiensMutation(s): 0 
Gene Names: CYP1A2
EC: 1.14.14.1
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P05177 (Homo sapiens)
Explore P05177 
Go to UniProtKB:  P05177
PHAROS:  P05177
GTEx:  ENSG00000140505 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05177
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

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

Download Ideal Coordinates CCD File 
C [auth A]2-PHENYL-4H-BENZO[H]CHROMEN-4-ONE
C19 H12 O2
VFMMPHCGEFXGIP-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BHF Binding MOAD:  2HI4 Ki: 25 (nM) from 1 assay(s)
BindingDB:  2HI4 Ki: 20 (nM) from 1 assay(s)
IC50: min: 3.8, max: 3.26e+4 (nM) from 23 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.223 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.63α = 90
b = 80.82β = 90
c = 175.82γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction
CCP4data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-02-20
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-18
    Changes: Refinement description
  • Version 1.4: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description