4I3Q

Crystal structure of human CYP3A4 coordinated to a water molecule


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.298 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.224 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir.

Sevrioukova, I.F.Poulos, T.L.

(2013) J Med Chem 56: 3733-3741

  • DOI: https://doi.org/10.1021/jm400288z
  • Primary Citation of Related Structures:  
    4I3Q, 4I4G, 4I4H

  • PubMed Abstract: 

    Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.


  • Organizational Affiliation

    Departments of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, United States. sevrioui@uci.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 3A4487Homo sapiensMutation(s): 0 
Gene Names: CYP3A4CYP3A3
EC: 1.14.13 (PDB Primary Data), 1.14.13.157 (PDB Primary Data), 1.14.13.32 (PDB Primary Data), 1.14.13.67 (PDB Primary Data), 1.14.13.97 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P08684 (Homo sapiens)
Explore P08684 
Go to UniProtKB:  P08684
PHAROS:  P08684
GTEx:  ENSG00000160868 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08684
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.298 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.224 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.11α = 90
b = 101.47β = 90
c = 130.54γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-04-24
    Type: Initial release
  • Version 1.1: 2013-05-01
    Changes: Database references
  • Version 1.2: 2013-05-22
    Changes: Database references
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description