Substrate Free Cytochrome P450 3A5 (CYP3A5)

Experimental Data Snapshot

  • Resolution: 2.20 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.211 

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This is version 1.4 of the entry. See complete history


Active-site differences between substrate-free and ritonavir-bound cytochrome P450 (CYP) 3A5 reveal plasticity differences between CYP3A5 and CYP3A4.

Hsu, M.H.Johnson, E.F.

(2019) J Biol Chem 294: 8015-8022

  • DOI: https://doi.org/10.1074/jbc.RA119.007928
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 

    Cytochrome P450 (CYP) 3A4 is a major contributor to hepatic drug and xenobiotic metabolism in human adults. The related enzyme CYP3A5 is also expressed in adult liver and has broader age and tissue distributions. However, CYP3A5 expression is low in most Caucasians because of the prevalence of an allele that leads to an incorrectly spliced mRNA and premature termination of translation. When expressed, CYP3A5 expands metabolic capabilities and can augment CYP3A4-mediated drug metabolism, thereby reducing drug efficacy and potentially requiring dose adjustments. The extensive role of CYP3A4 in drug metabolism reflects in part the plasticity of the substrate-free enzyme to enlarge its active site and accommodate very large substrates. We have previously shown that the structure of the CYP3A5-ritonavir complex differs substantially from that of the CYP3A4-ritonavir complex. To better understand whether these differences are conserved in other CYP3A5 structures and how they relate to differential plasticity, we determined the X-ray crystallographic structure of the CYP3A5 substrate-free complex to 2.20 Å resolution. We observed that this structure exhibits a much larger active site than substrate-free CYP3A4 and displays an open substrate access channel. This reflected in part a lower trajectory of the helix F-F' connector in CYP3A4 and more extensive π-CH interactions between phenylalanine residues forming the roof of the active-site cavity than in CYP3A5. Comparison with the CYP3A5-ritonavir complex confirmed conserved CYP3A5 structural features and indicated differences in plasticity between CYP3A4 and CYP3A5 that favor alternative ritonavir conformations.

  • Organizational Affiliation

    Department of Molecular Medicine, Scripps Research, La Jolla, California 92037.

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 3A5480Homo sapiensMutation(s): 0 
Gene Names: CYP3A5
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P20815 (Homo sapiens)
Explore P20815 
Go to UniProtKB:  P20815
PHAROS:  P20815
GTEx:  ENSG00000106258 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20815
Sequence Annotations
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Resolution: 2.20 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.211 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.67α = 90
b = 100.69β = 90
c = 136.02γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XDSdata scaling

Structure Validation

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Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01GM031001

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-03
    Type: Initial release
  • Version 1.1: 2019-04-10
    Changes: Data collection, Database references
  • Version 1.2: 2019-05-29
    Changes: Data collection, Database references
  • Version 1.3: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-11
    Changes: Data collection, Database references, Refinement description