2BBQ

STRUCTURAL BASIS FOR RECOGNITION OF POLYGLUTAMYL FOLATES BY THYMIDYLATE SYNTHASE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Work: 0.182 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structural basis for recognition of polyglutamyl folates by thymidylate synthase.

Kamb, A.Finer-Moore, J.Calvert, A.H.Stroud, R.M.

(1992) Biochemistry 31: 9883-9890

  • DOI: https://doi.org/10.1021/bi00156a005
  • Primary Citation of Related Structures:  
    2BBQ

  • PubMed Abstract: 

    Thymidylate synthase (TS) catalyzes the final step in the de novo synthesis of thymidine. In vivo TS binds a polyglutamyl cofactor, polyglutamyl methylenetetrahydrofolate (CH2-H4folate), which serves as a carbon donor. Glutamate residues on the cofactor contribute as much as 3.7 kcal to the interaction between the cofactor, substrate, and enzyme. Because many ligand/receptor interactions appear to be driven largely by hydrophobic forces, it is surprising that the addition of hydrophilic, soluble groups such as glutamates increases the affinity of the cofactor for TS. The structure of a polyglutamyl cofactor analog bound in ternary complex with deoxyuridine monophosphate (dUMP) and Escherichia coli TS reveals how the polyglutamyl moiety is positioned in TS and accounts in a qualitative way for the binding contributions of the different individual glutamate residues. The polyglutamyl moiety is not rigidly fixed by its interaction with the protein except for the first glutamate residue nearest the p-aminobenzoic acid ring of folate. Each additional glutamate is progressively more disordered than the previous one in the chain. The position of the second and third glutamate residues on the protein surface suggests that the polyglutamyl binding site could be utilized by a new family of inhibitors that might fill the binding area more effectively than polyglutamate.


  • Organizational Affiliation

    Department of Biochemistry and Biophysics, University of California, San Francisco 94143.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THYMIDYLATE SYNTHASE
A, B
264Escherichia coliMutation(s): 0 
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
PFG
Query on PFG

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]
10-PARPARGYL-5,8-DIDEAZAFOLATE-4-GLUTAMIC ACID
C39 H44 N8 O15
SASAWWASHFSVQE-QGMKSFRFSA-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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Work: 0.182 
  • R-Value Observed: 0.182 
  • Space Group: P 63
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 127.1α = 90
b = 127.1β = 90
c = 67.9γ = 120
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1994-01-31
    Type: Initial release
  • Version 1.1: 2008-03-24
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance