2XKR

Crystal Structure of Mycobacterium tuberculosis CYP142: A novel cholesterol oxidase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 

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This is version 1.4 of the entry. See complete history


Literature

Structural and Biochemical Characterization of Mycobacterium Tuberculosis Cyp142: Evidence for Multiple Cholesterol 27-Hydroxylase Activities in a Human Pathogen.

Driscoll, M.D.Mclean, K.J.Levy, C.W.Mast, N.Pikuleva, I.A.Lafite, P.Rigby, S.E.J.Leys, D.Munro, A.W.

(2010) J Biol Chem 285: 38270

  • DOI: https://doi.org/10.1074/jbc.M110.164293
  • Primary Citation of Related Structures:  
    2XKR

  • PubMed Abstract: 

    The Mycobacterium tuberculosis cytochrome P450 enzyme CYP142 is encoded in a large gene cluster involved in metabolism of host cholesterol. CYP142 was expressed and purified as a soluble, low spin P450 hemoprotein. CYP142 binds tightly to cholesterol and its oxidized derivative cholest-4-en-3-one, with extensive shift of the heme iron to the high spin state. High affinity for azole antibiotics was demonstrated, highlighting their therapeutic potential. CYP142 catalyzes either 27-hydroxylation of cholesterol/cholest-4-en-3-one or generates 5-cholestenoic acid/cholest-4-en-3-one-27-oic acid from these substrates by successive sterol oxidations, with the catalytic outcome dependent on the redox partner system used. The CYP142 crystal structure was solved to 1.6 Å, revealing a similar active site organization to the cholesterol-metabolizing M. tuberculosis CYP125, but having a near-identical organization of distal pocket residues to the branched fatty acid oxidizing M. tuberculosis CYP124. The cholesterol oxidizing activity of CYP142 provides an explanation for previous findings that ΔCYP125 strains of Mycobacterium bovis and M. bovis BCG cannot grow on cholesterol, because these strains have a defective CYP142 gene. CYP142 is revealed as a cholesterol 27-oxidase with likely roles in host response modulation and cholesterol metabolism.


  • Organizational Affiliation

    Manchester Interdisciplinary Biocentre, Faculty of Life Sciences, University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PUTATIVE CYTOCHROME P450 142398Mycobacterium tuberculosis H37RvMutation(s): 0 
EC: 1.14
UniProt
Find proteins for P9WPL5 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WPL5 
Go to UniProtKB:  P9WPL5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WPL5
Sequence Annotations
Expand
  • 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
PG4
Query on PG4

Download Ideal Coordinates CCD File 
C [auth A]TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.31α = 90
b = 65.46β = 90
c = 129.47γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-09-29
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-04-10
    Changes: Advisory, Data collection, Other, Source and taxonomy
  • Version 1.4: 2023-12-20
    Changes: Advisory, Data collection, Database references, Derived calculations, Other, Refinement description