3GWC

Crystal structure of Mycobacterium tuberculosis thymidylate synthase X bound to FdUMP and FAD


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Increasing the structural coverage of tuberculosis drug targets.

Baugh, L.Phan, I.Begley, D.W.Clifton, M.C.Armour, B.Dranow, D.M.Taylor, B.M.Muruthi, M.M.Abendroth, J.Fairman, J.W.Fox, D.Dieterich, S.H.Staker, B.L.Gardberg, A.S.Choi, R.Hewitt, S.N.Napuli, A.J.Myers, J.Barrett, L.K.Zhang, Y.Ferrell, M.Mundt, E.Thompkins, K.Tran, N.Lyons-Abbott, S.Abramov, A.Sekar, A.Serbzhinskiy, D.Lorimer, D.Buchko, G.W.Stacy, R.Stewart, L.J.Edwards, T.E.Van Voorhis, W.C.Myler, P.J.

(2015) Tuberculosis (Edinb) 95: 142-148

  • DOI: https://doi.org/10.1016/j.tube.2014.12.003
  • Primary Citation of Related Structures:  
    3GVC, 3GVG, 3GWC, 3H7F, 3H81, 3HE2, 3HWI, 3HWK, 3HZG, 3ICO, 3KHP, 3LLS, 3MOY, 3MPZ, 3MYB, 3NDN, 3NDO, 3NF4, 3NG3, 3NJD, 3NWO, 3O0M, 3O38, 3OC6, 3OC7, 3OI9, 3OKS, 3OME, 3P0T, 3P2Y, 3P4I, 3P4T, 3P5M, 3P85, 3PE8, 3PK0, 3PPI, 3PZY, 3Q1T, 3Q8N, 3QBP, 3QDF, 3QHA, 3QIV, 3QK8, 3QKA, 3QLJ, 3QMJ, 3QRE, 3QUA

  • PubMed Abstract: 

    High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.


  • Organizational Affiliation

    Seattle Structural Genomics Center for Infectious Disease, United States; Seattle Biomedical Research Institute, 307 Westlake Ave N, Suite 500, Seattle, WA 98109, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thymidylate synthase thyX
A, B, C, D, E
A, B, C, D, E, F, G, H
258Mycobacterium tuberculosisMutation(s): 0 
Gene Names: thyXRv2754cMT2824MTV002.19c
EC: 2.1.1.148
UniProt
Find proteins for P9WG57 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WG57 
Go to UniProtKB:  P9WG57
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WG57
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
I [auth A]
K [auth B]
M [auth C]
P [auth D]
R [auth E]
I [auth A],
K [auth B],
M [auth C],
P [auth D],
R [auth E],
T [auth F],
V [auth G],
X [auth H]
FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
UFP
Query on UFP

Download Ideal Coordinates CCD File 
J [auth A]
L [auth B]
N [auth C]
Q [auth D]
S [auth E]
J [auth A],
L [auth B],
N [auth C],
Q [auth D],
S [auth E],
U [auth F],
W [auth G],
Y [auth H]
5-FLUORO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE
C9 H12 F N2 O8 P
HFEKDTCAMMOLQP-RRKCRQDMSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
O [auth C]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.044α = 90
b = 78.447β = 96.8
c = 168.959γ = 90
Software Package:
Software NamePurpose
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-04-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2015-04-22
    Changes: Database references
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations