4J14

Crystal Structure of Human Cytochrome P450 CYP46A1 with Posaconazole Bound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.216 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1.

Mast, N.Zheng, W.Stout, C.D.Pikuleva, I.A.

(2013) Mol Pharmacol 84: 86-94

  • DOI: https://doi.org/10.1124/mol.113.085902
  • Primary Citation of Related Structures:  
    4J14

  • PubMed Abstract: 

    Although there are currently three generations of antifungal azoles on the market, even the third-generation agents show undesirable interactions with human cytochrome P450 (P450) enzymes. CYP46A1 is a cholesterol-metabolizing P450 in the brain that tightly binds a number of structurally distinct azoles. Previously, we determined the crystal structures of CYP46A1 in complex with voriconazole and clotrimazole, and in the present work we cocrystallized the P450 with posaconazole at 2.5 Å resolution. This long antifungal drug coordinates the P450 heme iron with the nitrogen atom of its terminal azole ring and adopts a linear configuration occupying the whole length of the substrate access channel and extending beyond the protein surface. Numerous drug-protein interactions determine the submicromolar Kd of posaconazole for CYP46A1. We compared the crystal structure of posaconazole-bound CYP46A1 with those of the P450 in complex with other drugs, including the antifungal voriconazole and clotrimazole. We also analyzed the accommodation of posaconazole in the active site of the target enzymes, CYPs 51, from several pathogenic species. These and the solution studies with different marketed azoles, collectively, allowed us to identify the determinants of tight azole binding to CYP46A1 and generate an overall picture of azole binding to this important P450. The data obtained suggest that development of CYP51-specific antifungal agents will continue to be a challenge. Therefore, structural understanding of the azole binding not only to CYPs 51 from the pathogenic species but also to different human P450s is required to deal efficiently with this challenge.


  • Organizational Affiliation

    Department of Ophthalmology and Visual Sciences, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. iap8@case.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cholesterol 24-hydroxylase456Homo sapiensMutation(s): 0 
Gene Names: CP46A_HUMANCYP46CYP46A1
EC: 1.14.13.98
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y6A2 (Homo sapiens)
Explore Q9Y6A2 
Go to UniProtKB:  Q9Y6A2
PHAROS:  Q9Y6A2
GTEx:  ENSG00000036530 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y6A2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
X2N Binding MOAD:  4J14 Kd: 30 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.216 
  • Space Group: I 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.64α = 90
b = 121.64β = 90
c = 143.39γ = 90
Software Package:
Software NamePurpose
ADSCdata 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: 2014-01-15
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description