5JA3

Mycobacterium tuberculosis Dihydrofolate Reductase complexed with beta- NADPH and 3'-(3-(2,4-diamino-6-ethylpyrimidin-5-yl)prop-2-yn-1-yl)-4'-methoxy-[1,1'-b iphenyl]-4-carboxylic acid (UCP1106)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.227 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis.

Hajian, B.Scocchera, E.Keshipeddy, S.G-Dayanandan, N.Shoen, C.Krucinska, J.Reeve, S.Cynamon, M.Anderson, A.C.Wright, D.L.

(2016) PLoS One 11: e0161740-e0161740

  • DOI: https://doi.org/10.1371/journal.pone.0161740
  • Primary Citation of Related Structures:  
    5JA3

  • PubMed Abstract: 

    Mycobacterium tuberculosis continues to cause widespread, life-threatening disease. In the last decade, this threat has grown dramatically as multi- and extensively-drug resistant (MDR and XDR) bacteria have spread globally and the number of agents that effectively treat these infections is significantly reduced. We have been developing the propargyl-linked antifolates (PLAs) as potent inhibitors of the essential enzyme dihydrofolate reductase (DHFR) from bacteria and recently found that charged PLAs with partial zwitterionic character showed improved mycobacterial cell permeability. Building on a hypothesis that these PLAs may penetrate the outer membrane of M. tuberculosis and inhibit the essential cytoplasmic DHFR, we screened a group of PLAs for antitubercular activity. In this work, we identified several PLAs as potent inhibitors of the growth of M. tuberculosis with several of the compounds exhibiting minimum inhibition concentrations equal to or less than 1 μg/mL. Furthermore, two of the compounds were very potent inhibitors of MDR and XDR strains. A high resolution crystal structure of one PLA bound to DHFR from M. tuberculosis reveals the interactions of the ligands with the target enzyme.


  • Organizational Affiliation

    Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrofolate reductase
A, B, C, D
159Mycobacterium tuberculosisMutation(s): 0 
Gene Names: folAdfrAMT2833
EC: 1.5.1.3
UniProt
Find proteins for P9WNX1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WNX1 
Go to UniProtKB:  P9WNX1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WNX1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
U06 Binding MOAD:  5JA3 IC50: 173 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.227 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.612α = 90.07
b = 60.444β = 90.06
c = 60.472γ = 89.93
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



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 StatesAI111957

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-24
    Type: Initial release
  • Version 1.1: 2016-09-14
    Changes: Database references
  • Version 1.2: 2017-09-20
    Changes: Author supporting evidence, Derived calculations
  • Version 1.3: 2017-11-01
    Changes: Author supporting evidence
  • Version 1.4: 2019-12-11
    Changes: Author supporting evidence
  • Version 1.5: 2024-03-06
    Changes: Data collection, Database references