3FYV

Staph. aureus DHFR complexed with NADPH and AR-102


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.224 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Inhibitory properties and X-ray crystallographic study of the binding of AR-101, AR-102 and iclaprim in ternary complexes with NADPH and dihydrofolate reductase from Staphylococcus aureus

Oefner, C.Parisi, S.Schulz, H.Lociuro, S.Dale, G.E.

(2009) Acta Crystallogr D Biol Crystallogr 65: 751-757

  • DOI: https://doi.org/10.1107/S0907444909013936
  • Primary Citation of Related Structures:  
    3FY8, 3FY9, 3FYV, 3FYW

  • PubMed Abstract: 

    Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative. Iclaprim exhibits potent bactericidal activity against major Gram-positive pathogens, notably methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) phenotypes, including TMP-resistant strains. The inhibition properties of racemic iclaprim and of the two enantiomers, termed AR-101 and AR-102, towards S. aureus wild-type DHFR and TMP-resistant F98Y mutant DHFR were determined and compared. Similar to TMP, AR-101, AR-102 and iclaprim are all competitive inhibitors with respect to the substrate dihydrofolate. Iclaprim, AR-101 and AR-102 demonstrated little or no difference in activity towards these enzymes and were significantly more potent than TMP. The crystal structures of S. aureus DHFR and F98Y mutant DHFR were determined as ternary complexes with NADPH and either AR-101, AR-102 or iclaprim. The binding modes of the inhibitors were analysed and compared. The X-ray crystallographic data explain the binding modes of all molecules well and can be used to rationalize the equipotent affinity of AR-101, AR-102 and iclaprim, which is also reflected in their antibacterial properties.


  • Organizational Affiliation

    Arpida Ltd, 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
XCF Binding MOAD:  3FYV Ki: 0.22 (nM) from 1 assay(s)
BindingDB:  3FYV IC50: 2.9 (nM) from 1 assay(s)
I2H BindingDB:  3FYV Ki: min: 0.08, max: 0.08 (nM) from 2 assay(s)
IC50: min: 2.2, max: 7 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.224 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.093α = 90
b = 79.093β = 90
c = 107.781γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
AMoREphasing
REFMACrefinement
DENZOdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-08-04 
  • Deposition Author(s): Oefner, C.

Revision History  (Full details and data files)

  • Version 1.0: 2009-08-04
    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