2Q9F

Crystal structure of human cytochrome P450 46A1 in complex with cholesterol-3-sulphate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.183 

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 HEMClick on this verticalbar to view detailsBest fitted C3SClick on this verticalbar to view details

This is version 1.2 of the entry. See complete history


Literature

Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain.

Mast, N.White, M.A.Bjorkhem, I.Johnson, E.F.Stout, C.D.Pikuleva, I.A.

(2008) Proc Natl Acad Sci U S A 105: 9546-9551

  • DOI: https://doi.org/10.1073/pnas.0803717105
  • Primary Citation of Related Structures:  
    2Q9F, 2Q9G

  • PubMed Abstract: 

    By converting cholesterol to 24S-hydroxycholesterol, cytochrome P450 46A1 (CYP46A1) initiates the major pathway for cholesterol removal from the brain. Two crystal structures of CYP46A1 were determined. First is the 1.9-A structure of CYP46A1 complexed with a high-affinity substrate cholesterol 3-sulfate (CH-3S). The second structure is that of the substrate-free CYP46A1 at 2.4-A resolution. CH-3S is bound in the productive orientation and occupies the entire length of the banana-shaped hydrophobic active-site cavity. A unique helix B'-C loop insertion (residues 116-120) contributes to positioning cholesterol for oxygenation catalyzed by CYP46A1. A comparison with the substrate-free structure reveals substantial substrate-induced conformational changes in CYP46A1 and suggests that structurally distinct compounds could bind in the enzyme active site. In vitro assays were performed to characterize the effect of different therapeutic agents on cholesterol hydroxylase activity of purified full-length recombinant CYP46A1, and several strong inhibitors and modest coactivators of CYP46A1 were identified. Structural and biochemical data provide evidence that CYP46A1 activity could be altered by exposure to some therapeutic drugs and potentially other xenobiotics.


  • Organizational Affiliation

    Department of Pharmacology and Toxicology, The Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 46A1456Homo sapiensMutation(s): 0 
Gene Names: CYP46A1CYP46
EC: 1.14.13.98 (PDB Primary Data), 1.14.14.25 (UniProt)
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
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
C [auth A]PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
C3S
Query on C3S

Download Ideal Coordinates CCD File 
D [auth A]CHOLEST-5-EN-3-YL HYDROGEN SULFATE
C27 H46 O4 S
BHYOQNUELFTYRT-DPAQBDIFSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
B [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.183 
  • Space Group: I 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.85α = 90
b = 121.85β = 90
c = 144.03γ = 90
Software Package:
Software NamePurpose
SOLVEphasing
CNSrefinement
Blu-Icedata collection
MOSFLMdata reduction
SCALAdata scaling

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 HEMClick on this verticalbar to view detailsBest fitted C3SClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-06-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations