4CK8

STEROL 14-ALPHA DEMETHYLASE (CYP51)FROM TRYPANOSOMA CRUZI IN COMPLEX WITH (R)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl 4-(4-(3,4- dichlorophenyl)piperazin-1-yl)phenylcarbamate (LFD)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.62 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.235 
  • R-Value Observed: 0.238 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma Cruzi Sterol 14Alpha-Demethylase: Two Regions of the Enzyme Molecule Potentiate its Inhibition.

Friggeri, L.Hargrove, T.Y.Rachakonda, G.Williams, A.D.Wawrzak, Z.Di Santo, R.De Vita, D.Waterman, M.R.Tortorella, S.Villalta, F.Lepesheva, G.I.

(2014) J Med Chem 57: 6704

  • DOI: https://doi.org/10.1021/jm500739f
  • Primary Citation of Related Structures:  
    4CK8, 4CK9, 4CKA

  • PubMed Abstract: 

    Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of β-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50=1.2 nM, vs (S)-2/(S)-3, EC50=1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs.


  • Organizational Affiliation

    Department of Biochemistry, School of Medicine, Vanderbilt University , Nashville, Tennessee 37232, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
STEROL 14-ALPHA DEMETHYLASE
A, B
460Trypanosoma cruziMutation(s): 0 
EC: 1.14.13.70
UniProt
Find proteins for Q7Z1V1 (Trypanosoma cruzi (strain CL Brener))
Explore Q7Z1V1 
Go to UniProtKB:  Q7Z1V1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ7Z1V1
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
LFD
Query on LFD

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]
(1R)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl {4-[4-(3,4-dichlorophenyl)piperazin-1-yl]phenyl}carbamate
C28 H25 Cl4 N5 O2
RKYWJGOKHMLHHS-MHZLTWQESA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.62 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.235 
  • R-Value Observed: 0.238 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.9α = 90
b = 137.18β = 90
c = 152.43γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-30
    Type: Initial release
  • Version 1.1: 2014-08-27
    Changes: Database references
  • Version 1.2: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description