3FRF

S. aureus DHFR complexed with NADPH and iclaprim


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.230 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Increased hydrophobic interactions of iclaprim with Staphylococcus aureus dihydrofolate reductase are responsible for the increase in affinity and antibacterial activity

Oefner, C.Bandera, M.Haldimann, A.Laue, H.Schulz, H.Mukhija, S.Parisi, S.Weiss, L.Lociuro, S.Dale, G.E.

(2009) J Antimicrob Chemother 63: 687-698

  • DOI: https://doi.org/10.1093/jac/dkp024
  • Primary Citation of Related Structures:  
    3FRA, 3FRB, 3FRD, 3FRE, 3FRF

  • PubMed Abstract: 

    Iclaprim is a novel 2,4-diaminopyrimidine that exhibits potent, rapid bactericidal activity against major Gram-positive pathogens, including methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus, and is currently in clinical development for the treatment of complicated skin and skin structure infections. An understanding of the known mechanism of resistance to trimethoprim led to the design of this new inhibitor, with improved affinity towards dihydrofolate reductase (DHFR) from S. aureus and clinically useful activity against S. aureus including isolates resistant to trimethoprim. The objective of this study was to characterize the mode of action of iclaprim and its inhibitory properties against DHFR.


  • Organizational Affiliation

    Arpida AG, Duggingerstrasse 23, CH-4153 Reinach, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrofolate reductaseA [auth X]158Staphylococcus aureusMutation(s): 0 
Gene Names: folA
EC: 1.5.1.3
UniProt
Find proteins for P0A017 (Staphylococcus aureus)
Explore P0A017 
Go to UniProtKB:  P0A017
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0A017
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NDP
Query on NDP

Download Ideal Coordinates CCD File 
B [auth X]NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
XCF
Query on XCF

Download Ideal Coordinates CCD File 
C [auth X]5-[[(2R)-2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl]methyl]pyrimidine-2,4-diamine
C19 H22 N4 O3
HWJPWWYTGBZDEG-AWEZNQCLSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
I2H BindingDB:  3FRF Ki: min: 0.08, max: 0.08 (nM) from 2 assay(s)
IC50: min: 2.2, max: 7 (nM) from 3 assay(s)
XCF Binding MOAD:  3FRF Ki: 3 (nM) from 1 assay(s)
BindingDB:  3FRF IC50: 2.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.230 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.279α = 90
b = 79.279β = 90
c = 108.165γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
AMoREphasing
REFMACrefinement
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-12
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2013-11-20
    Changes: Non-polymer description
  • Version 1.3: 2024-03-20
    Changes: Data collection, Database references, Derived calculations