2KCE

BINDING OF THE ANTICANCER DRUG ZD1694 TO E. COLI THYMIDYLATE SYNTHASE: ASSESSING SPECIFICITY AND AFFINITY


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Binding of the anticancer drug ZD1694 to E. coli thymidylate synthase: assessing specificity and affinity.

Rutenber, E.E.Stroud, R.M.

(1996) Structure 4: 1317-1324

  • DOI: https://doi.org/10.1016/s0969-2126(96)00139-6
  • Primary Citation of Related Structures:  
    2KCE

  • PubMed Abstract: 

    Thymidylate synthase (TS) catalyzes the reductive methylation of deoxyuridine monophosphate (dUMP) by 5, 10-methylenetetrahydrofolate (CH2H4folate) to form deoxythymidine monophosphate (dTMP) and dihydrofolate (H2folate). The essential role of TS in the cell life cycle makes it an attractive target for the development of substrate and cofactor-based inhibitors that may find efficacy as anticancer and antiproliferative drugs. Antifolates that compete specifically with the binding of CH2H4 folate include the cofactor analog CB3717 (10-propargyl-5,8-dideazafolate). However, the development of potent cofactor analog inhibitors of TS, such as CB3717, as drugs has been slowed by their toxicity, which often becomes apparent as hepatic and renal toxicity mediated by the specific chemistry of the compound. Attempts to abolish toxicity in human patients while preserving potency against the target enzyme, have led to the development of ZD1694, which has already shown significant activity against colorectal tumours.


  • Organizational Affiliation

    Department of Biochemistry and Biophysics, University of California at San Francisco, 94143-0448, USA. stroud@msg.ucsf.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THYMIDYLATE SYNTHASE
A, B
264Escherichia coliMutation(s): 0 
Gene Names: THYA
EC: 2.1.1.45
UniProt
Find proteins for P0A884 (Escherichia coli (strain K12))
Explore P0A884 
Go to UniProtKB:  P0A884
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0A884
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
D16
Query on D16

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

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
2'-DEOXYURIDINE 5'-MONOPHOSPHATE
C9 H13 N2 O8 P
JSRLJPSBLDHEIO-SHYZEUOFSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
D16 PDBBind:  2KCE Ki: 670 (nM) from 1 assay(s)
Binding MOAD:  2KCE Ki: 670 (nM) from 1 assay(s)
BindingDB:  2KCE IC50: 2300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • Space Group: P 63
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 126.8α = 90
b = 126.8β = 90
c = 67.56γ = 120
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
SIEMENSdata reduction
SIEMENSdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1997-11-19
    Type: Initial release
  • Version 1.1: 2008-03-24
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2012-10-10
    Changes: Non-polymer description