RCSB PDB - 7KVP: Human CYP3A4 bound to an inhibitor

 7KVP

Human CYP3A4 bound to an inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.230 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted X6JClick on this verticalbar to view details

This is version 1.2 of the entry. See complete history


Literature

Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength.

Samuels, E.R.Sevrioukova, I.F.

(2021) Int J Mol Sci 22

  • DOI: https://doi.org/10.3390/ijms22020852
  • Primary Citation of Related Structures:  
    7KVH, 7KVI, 7KVJ, 7KVK, 7KVM, 7KVN, 7KVO, 7KVP, 7KVQ, 7KVS

  • PubMed Abstract: 

    Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug-drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure-activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R 1 /R 2 side-groups as phenyls or R 1 -phenyl/R 2 -indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl-ethyl to pyridyl-propyl, was beneficial and markedly improved K s , IC 50 and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound, 3h , was among the best inhibitors designed so far and overall, the strongest binder (K s and IC 50 of 0.007 and 0.090 µM, respectively). 3h was the fourth structurally simpler inhibitor superior to ritonavir, which further demonstrates the power of our approach.


  • Organizational Affiliation

    Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697-3900, USA.


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: 1.14.14.1 (PDB Primary Data), 1.14.14.56 (PDB Primary Data), 1.14.14.73 (PDB Primary Data), 1.14.14.55 (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 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
X6J (Subject of Investigation/LOI)
Query on X6J

Download Ideal Coordinates CCD File 
C [auth A]tert-butyl [(2R)-1-(naphthalen-1-yl)-3-{[(2S)-1-oxo-3-phenyl-1-{[3-(pyridin-3-yl)propyl]amino}propan-2-yl]sulfanyl}propan-2-yl]carbamate
C35 H41 N3 O3 S
XDOKSTKEPWQDPB-BHYZAODMSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.230 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.19α = 90
b = 102.34β = 90
c = 128.3γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted X6JClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)United StatesES025767

Revision History  (Full details and data files)

  • Version 1.0: 2021-01-20
    Type: Initial release
  • Version 1.1: 2021-02-03
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Database references, Refinement description