4D78

Cytochrome P450 3A4 bound to an inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structure-Based Inhibitor Design for Evaluation of a Cyp3A4 Pharmacophore Model.

Kaur, P.Chamberlin, R.Poulos, T.L.Sevrioukova, I.F.

(2016) J Med Chem 59: 4210

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01146
  • Primary Citation of Related Structures:  
    4D6Z, 4D75, 4D78, 4D7D

  • PubMed Abstract: 

    Human cytochrome P450 3A4 (CYP3A4) is a key xenobiotic-metabolizing enzyme that oxidizes and clears the majority of drugs. CYP3A4 inhibition may lead to drug-drug interactions, toxicity, and other adverse effects but, in some cases, could be beneficial and enhance therapeutic efficiency of coadministered pharmaceuticals that are metabolized by CYP3A4. On the basis of our investigations of analogs of ritonavir, a potent CYP3A4 inactivator and pharmacoenhancer, we have built a pharmacophore model for a CYP3A4-specific inhibitor. This study is the first attempt to test this model using a set of rationally designed compounds. The functional and structural data presented here agree well with the proposed pharmacophore. In particular, we confirmed the importance of a flexible backbone, the H-bond donor/acceptor moiety, and aromaticity of the side group analogous to Phe-2 of ritonavir and demonstrated the leading role of hydrophobic interactions at the sites adjacent to the heme and phenylalanine cluster in the ligand binding process. The X-ray structures of CYP3A4 bound to the rationally designed inhibitors provide deeper insights into the mechanism of the CYP3A4-ligand interaction. Most importantly, two of our compounds (15a and 15b) that are less complex than ritonavir have comparable submicromolar affinity and inhibitory potency for CYP3A4 and, thus, could serve as templates for synthesis of second generation inhibitors for further evaluation and optimization of the pharmacophore model.


  • Organizational Affiliation

    Departments of †Pharmaceutical Sciences, ‡Chemistry, and §Molecular Biology and Biochemistry, University of California-Irvine , Irvine, California 92697, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CYTOCHROME P450 3A4487Homo sapiensMutation(s): 0 
EC: 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
Expand
  • Reference Sequence
Small Molecules
Ligands 3 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
J9K
Query on J9K

Download Ideal Coordinates CCD File 
C [auth A]tert-butyl [(2S)-1-({3-oxo-3-[(pyridin-3-ylmethyl)amino]propyl}sulfanyl)-3-phenylpropan-2-yl]carbamate
C23 H31 N3 O3 S
MVQZDJDMEHCEJW-FQEVSTJZSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
J9K BindingDB:  4D78 Kd: 900 (nM) from 1 assay(s)
IC50: 520 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.197 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.92α = 90
b = 100.36β = 90
c = 124.75γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-23
    Type: Initial release
  • Version 1.1: 2015-09-30
    Changes: Database references
  • Version 1.2: 2016-05-25
    Changes: Database references
  • Version 1.3: 2019-05-08
    Changes: Data collection, Experimental preparation, Other
  • Version 1.4: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description