1M78

CANDIDA ALBICANS DIHYDROFOLATE REDUCTASE COMPLEXED WITH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (NADPH) AND 5-CHLORYL-2,4,6-QUINAZOLINETRIAMINE (GW1225)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Work: 0.156 
  • R-Value Observed: 0.156 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

X-Ray Crystallographic Studies of Candida Albicans Dihydrofolate Reductase. High Resolution Structures of the Holoenzyme and an Inhibited Ternary Complex.

Whitlow, M.Howard, A.J.Stewart, D.Hardman, K.D.Kuyper, L.F.Baccanari, D.P.Fling, M.E.Tansik, R.L.

(1997) J Biol Chem 272: 30289-30298

  • DOI: https://doi.org/10.1074/jbc.272.48.30289
  • Primary Citation of Related Structures:  
    1AI9, 1AOE, 1M78, 1M79, 1M7A

  • PubMed Abstract: 

    The recent rise in systemic fungal infections has created a need for the development of new antifungal agents. As part of an effort to provide therapeutically effective inhibitors of fungal dihydrofolate reductase (DHFR), we have cloned, expressed, purified, crystallized, and determined the three-dimensional structure of Candida albicans DHFR. The 192-residue enzyme, which was expressed in Escherichia coli and purified by methotrexate affinity and cation exchange chromatography, was 27% identical to human DHFR. Crystals of C. albicans DHFR were grown as the holoenzyme complex and as a ternary complex containing a pyrroloquinazoline inhibitor. Both complexes crystallized with two molecules in the asymmetric unit in space group P21. The final structures had R-factors of 0.199 at 1.85-A resolution and 0.155 at 1.60-A resolution, respectively. The enzyme fold was similar to that of bacterial and vertebrate DHFR, and the binding of a nonselective diaminopyrroloquinazoline inhibitor and the interactions of NADPH with protein were typical of ligand binding to other DHFRs. However, the width of the active site cleft of C. albicans DHFR was significantly larger than that of the human enzyme, providing a basis for the design of potentially selective inhibitors.


  • Organizational Affiliation

    Genex Corporation, Protein Engineering Department, Gaithersburg, Maryland 20877, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DIHYDROFOLATE REDUCTASE
A, B
192Candida albicansMutation(s): 0 
Gene Names: DFR1
EC: 1.5.1.3
UniProt
Find proteins for P22906 (Candida albicans)
Explore P22906 
Go to UniProtKB:  P22906
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22906
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
CLZ Binding MOAD:  1M78 IC50: 52 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Work: 0.156 
  • R-Value Observed: 0.156 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 76.91α = 90
b = 67.28β = 93.07
c = 38.49γ = 90
Software Package:
Software NamePurpose
X-GENdata reduction
FRODOmodel building
PROFFTrefinement
X-GENdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-03-04
    Type: Initial release
  • Version 1.1: 2008-04-28
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 2.0: 2023-08-23
    Changes: Advisory, Data collection, Database references, Derived calculations, Non-polymer description, Refinement description, Structure summary