4KLX

Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in an open conformation.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.23 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.183 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Mycobacterium tuberculosis Dihydrofolate Reductase Reveals Two Conformational States and a Possible Low Affinity Mechanism to Antifolate Drugs.

Dias, M.V.Tyrakis, P.Domingues, R.R.Paes Leme, A.F.Blundell, T.L.

(2014) Structure 22: 94-103

  • DOI: https://doi.org/10.1016/j.str.2013.09.022
  • Primary Citation of Related Structures:  
    4KL9, 4KLX, 4KM0, 4KM2, 4KNE

  • PubMed Abstract: 

    Inhibition of the biosynthesis of tetrahydrofolate (THF) has long been a focus in the treatment of both cancer and infectious diseases. Dihydrofolate reductase (DHFR), which catalyzes the last step, is one of the most thoroughly explored targets of this pathway, but there are no DHFR inhibitors used for tuberculosis treatment. Here, we report a structural, site-directed mutagenesis and calorimetric analysis of Mycobacterium tuberculosis DHFR (MtDHFR) in complex with classical DHFR inhibitors. Our study provides insights into the weak inhibition of MtDHFR by trimethoprim and other antifolate drugs, such as pyrimethamine and cycloguanil. The construction of the mutant Y100F, together with calorimetric studies, gives insights into low affinity of MtDHFR for classical DHFR inhibitors. Finally, the structures of MtDHFR in complex with pyrimethamine and cycloguanil define important interactions in the active site and provide clues to the more effective design of antibiotics targeted against MtDHFR.


  • Organizational Affiliation

    Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QA, UK; Laboratório Nacional de Biociências (LNBio), Centro de Nacional de Pesquisa em Energia e Materiais, Campinas, (CNPEM), São Paulo 13083-100, Brazil. Electronic address: bertacine@gmail.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrofolate reductase
A, B
179Mycobacterium tuberculosisMutation(s): 0 
Gene Names: dfrAfolAH37RvMT2833MTV002.28cRv2763c
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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ATR
Query on ATR

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
2'-MONOPHOSPHOADENOSINE-5'-DIPHOSPHATE
C10 H16 N5 O13 P3
YPTPYQSAVGGMFN-KQYNXXCUSA-N
ETE
Query on ETE

Download Ideal Coordinates CCD File 
D [auth A]2-{2-[2-2-(METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL
C9 H20 O5
ZNYRFEPBTVGZDN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.23 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.183 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.41α = 90
b = 63.06β = 100.82
c = 78.16γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
ADSCdata collection
MOSFLMdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-12-25
    Type: Initial release
  • Version 1.1: 2014-01-29
    Changes: Database references
  • Version 1.2: 2018-01-24
    Changes: Structure summary
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations