5TZ1

Crystal structure of sterol 14-alpha demethylase (CYP51) from Candida albicans in complex with the tetrazole-based antifungal drug candidate VT1161 (VT1)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.218 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structural analyses of Candida albicans sterol 14 alpha-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis.

Hargrove, T.Y.Friggeri, L.Wawrzak, Z.Qi, A.Hoekstra, W.J.Schotzinger, R.J.York, J.D.Guengerich, F.P.Lepesheva, G.I.

(2017) J Biol Chem 292: 6728-6743

  • DOI: https://doi.org/10.1074/jbc.M117.778308
  • Primary Citation of Related Structures:  
    5FSA, 5TZ1

  • PubMed Abstract: 

    With some advances in modern medicine (such as cancer chemotherapy, broad exposure to antibiotics, and immunosuppression), the incidence of opportunistic fungal pathogens such as Candida albicans has increased. Cases of drug resistance among these pathogens have become more frequent, requiring the development of new drugs and a better understanding of the targeted enzymes. Sterol 14α-demethylase (CYP51) is a cytochrome P450 enzyme required for biosynthesis of sterols in eukaryotic cells and is the major target of clinical drugs for managing fungal pathogens, but some of the CYP51 key features important for rational drug design have remained obscure. We report the catalytic properties, ligand-binding profiles, and inhibition of enzymatic activity of C. albicans CYP51 by clinical antifungal drugs that are used systemically (fluconazole, voriconazole, ketoconazole, itraconazole, and posaconazole) and topically (miconazole and clotrimazole) and by a tetrazole-based drug candidate, VT-1161 (oteseconazole: ( R )-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol). Among the compounds tested, the first-line drug fluconazole was the weakest inhibitor, whereas posaconazole and VT-1161 were the strongest CYP51 inhibitors. We determined the X-ray structures of C. albicans CYP51 complexes with posaconazole and VT-1161, providing a molecular mechanism for the potencies of these drugs, including the activity of VT-1161 against Candida krusei and Candida glabrata , pathogens that are intrinsically resistant to fluconazole. Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broad-spectrum antifungals.


  • Organizational Affiliation

    From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Sterol 14-alpha demethylase
A, B
490Candida albicansMutation(s): 2 
Gene Names: CYP51ERG11
EC: 1.14.13.70
Membrane Entity: Yes 
UniProt
Find proteins for P10613 (Candida albicans (strain SC5314 / ATCC MYA-2876))
Explore P10613 
Go to UniProtKB:  P10613
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP10613
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 
C [auth A],
E [auth B]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
VT1
Query on VT1

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]
(R)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol
C23 H16 F7 N5 O2
IDUYJRXRDSPPRC-NRFANRHFSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
VT1 Binding MOAD:  5TZ1 Kd: 20.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.218 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 177.64α = 90
b = 71.44β = 96.63
c = 79.19γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data collection
HKL-2000data scaling
xia2data scaling
xia2data reduction
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: 2017-03-15
    Type: Initial release
  • Version 1.1: 2017-03-22
    Changes: Database references
  • Version 1.2: 2017-05-03
    Changes: Database references
  • Version 1.3: 2017-11-22
    Changes: Refinement description
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description