1HVY

Human thymidylate synthase complexed with dUMP and Raltitrexed, an antifolate drug, is in the closed conformation


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.201 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug

Phan, J.Koli, S.Minor, W.Dunlap, R.B.Berger, S.H.Lebioda, L.

(2001) Biochemistry 40: 1897-1902

  • DOI: https://doi.org/10.1021/bi002413i
  • Primary Citation of Related Structures:  
    1HVY

  • PubMed Abstract: 

    Thymidylate synthase (TS) is a major target in the chemotherapy of colorectal cancer and some other neoplasms while raltitrexed (Tomudex, ZD1694) is an antifolate inhibitor of TS approved for clinical use in several European countries. The crystal structure of the complex between recombinant human TS, dUMP, and raltitrexed has been determined at 1.9 A resolution. In contrast to the situation observed in the analogous complex of the rat TS, the enzyme is in the closed conformation and a covalent bond between the catalytic Cys 195 and dUMP is present in both subunits. This mode of ligand binding is similar to that of the analogous complex of the Escherichia coli enzyme. The only major differences observed are a direct hydrogen bond between His 196 and the O4 atom of dUMP and repositioning of the side chain of Tyr 94 by about 2 A. The thiophene ring of the drug is disordered between two parallel positions.


  • Organizational Affiliation

    Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 92908, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THYMIDYLATE SYNTHASE
A, B, C, D
288Homo sapiensMutation(s): 1 
EC: 2.1.1.45
UniProt & NIH Common Fund Data Resources
Find proteins for P04818 (Homo sapiens)
Explore P04818 
Go to UniProtKB:  P04818
PHAROS:  P04818
GTEx:  ENSG00000176890 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04818
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
D16
Query on D16

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C],
N [auth D]
TOMUDEX
C21 H22 N4 O6 S
IVTVGDXNLFLDRM-HNNXBMFYSA-N
UMP
Query on UMP

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C],
O [auth D]
2'-DEOXYURIDINE 5'-MONOPHOSPHATE
C9 H13 N2 O8 P
JSRLJPSBLDHEIO-SHYZEUOFSA-N
BME
Query on BME

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B],
M [auth C],
P [auth D]
BETA-MERCAPTOETHANOL
C2 H6 O S
DGVVWUTYPXICAM-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A, B, C, D
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
Binding Affinity Annotations 
IDSourceBinding Affinity
D16 PDBBind:  1HVY IC50: 290 (nM) from 1 assay(s)
BindingDB:  1HVY IC50: min: 9, max: 2.90e+4 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.201 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.849α = 70.23
b = 70.495β = 83.29
c = 74.533γ = 73.28
Software Package:
Software NamePurpose
SCALEPACKdata scaling
CNSrefinement
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-01-31
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2012-10-10
    Changes: Non-polymer description
  • Version 1.4: 2017-10-04
    Changes: Refinement description
  • Version 1.5: 2022-04-13
    Changes: Database references, Derived calculations, Structure summary