7T7S

R-27 in Complex with S. aureus DHFR and tricyclic-NADPH (tNADPH)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.187 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus.

Wang, S.Reeve, S.M.Holt, G.T.Ojewole, A.A.Frenkel, M.S.Gainza, P.Keshipeddy, S.Fowler, V.G.Wright, D.L.Donald, B.R.

(2022) PLoS Comput Biol 18: e1009855-e1009855

  • DOI: https://doi.org/10.1371/journal.pcbi.1009855
  • Primary Citation of Related Structures:  
    7T7Q, 7T7S

  • PubMed Abstract: 

    Antimicrobial resistance presents a significant health care crisis. The mutation F98Y in Staphylococcus aureus dihydrofolate reductase (SaDHFR) confers resistance to the clinically important antifolate trimethoprim (TMP). Propargyl-linked antifolates (PLAs), next generation DHFR inhibitors, are much more resilient than TMP against this F98Y variant, yet this F98Y substitution still reduces efficacy of these agents. Surprisingly, differences in the enantiomeric configuration at the stereogenic center of PLAs influence the isomeric state of the NADPH cofactor. To understand the molecular basis of F98Y-mediated resistance and how PLAs' inhibition drives NADPH isomeric states, we used protein design algorithms in the osprey protein design software suite to analyze a comprehensive suite of structural, biophysical, biochemical, and computational data. Here, we present a model showing how F98Y SaDHFR exploits a different anomeric configuration of NADPH to evade certain PLAs' inhibition, while other PLAs remain unaffected by this resistance mechanism.


  • Organizational Affiliation

    Department of Computer Science, Duke University, Durham, North Carolina, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrofolate reductaseA [auth X]157Staphylococcus 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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
06U BindingDB:  7T7S Ki: 2.8 (nM) from 1 assay(s)
IC50: 19 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.187 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.875α = 90
b = 78.875β = 90
c = 107.993γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI104841
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM078031
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM118543

Revision History  (Full details and data files)

  • Version 1.0: 2022-02-02
    Type: Initial release
  • Version 1.1: 2023-08-16
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-18
    Changes: Refinement description