3JUS

Crystal structure of human lanosterol 14alpha-demethylase (CYP51) in complex with econazole


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.206 

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This is version 2.1 of the entry. See complete history


Literature

Structural basis of human CYP51 inhibition by antifungal azoles.

Strushkevich, N.Usanov, S.A.Park, H.W.

(2010) J Mol Biol 397: 1067-1078

  • DOI: https://doi.org/10.1016/j.jmb.2010.01.075
  • Primary Citation of Related Structures:  
    3JUS, 3JUV, 3LD6

  • PubMed Abstract: 

    The obligatory step in sterol biosynthesis in eukaryotes is demethylation of sterol precursors at the C14-position, which is catalyzed by CYP51 (sterol 14-alpha demethylase) in three sequential reactions. In mammals, the final product of the pathway is cholesterol, while important intermediates, meiosis-activating sterols, are produced by CYP51. Three crystal structures of human CYP51, ligand-free and complexed with antifungal drugs ketoconazole and econazole, were determined, allowing analysis of the molecular basis for functional conservation within the CYP51 family. Azole binding occurs mostly through hydrophobic interactions with conservative residues of the active site. The substantial conformational changes in the B' helix and F-G loop regions are induced upon ligand binding, consistent with the membrane nature of the protein and its substrate. The access channel is typical for mammalian sterol-metabolizing P450 enzymes, but is different from that observed in Mycobacterium tuberculosis CYP51. Comparison of the azole-bound structures provides insight into the relative binding affinities of human and bacterial P450 enzymes to ketoconazole and fluconazole, which can be useful for the rational design of antifungal compounds and specific modulators of human CYP51.


  • Organizational Affiliation

    Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, Canada. natstrush@gmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Lanosterol 14-alpha demethylase
A, B
461Homo sapiensMutation(s): 0 
Gene Names: CYP51CYP51A1
EC: 1.14.13.70
UniProt & NIH Common Fund Data Resources
Find proteins for Q16850 (Homo sapiens)
Explore Q16850 
Go to UniProtKB:  Q16850
PHAROS:  Q16850
GTEx:  ENSG00000001630 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16850
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
Cycloheptakis-(1-4)-(alpha-D-glucopyranose)
C, D
7N/A
Glycosylation Resources
GlyTouCan:  G01435GL
GlyCosmos:  G01435GL
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
ECL BindingDB:  3JUS IC50: 50 (nM) from 1 assay(s)
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.206 
  • Space Group: P 4 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 146.626α = 90
b = 146.626β = 90
c = 110.56γ = 90
Software Package:
Software NamePurpose
CCP4model building
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
CCP4phasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-03-02
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-08-01
    Changes: Non-polymer description
  • Version 1.3: 2019-04-10
    Changes: Data collection, Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2023-09-06
    Changes: Data collection, Database references, Refinement description, Structure summary