4EB4: Crystal Structure Of Mouse Thymidylate Synthase In Ternary Complex With Dump And Tomudex

Citation:
Abstract
The crystal structure of mouse thymidylate synthase (mTS) in complex with substrate dUMP and antifolate inhibitor Raltitrexed is reported. The structure reveals, for the first time in the group of mammalian TS structures, a well-ordered segment of 13 N-terminal amino acids, whose ordered conformation is stabilized due to specific crystal packing. The structure consists of two homodimers, differing in conformation, one being more closed (dimer AB) and thus supporting tighter binding of ligands, and the other being more open (dimer CD) and thus allowing weaker binding of ligands. This difference indicates an asymmetrical effect of the binding of Raltitrexed to two independent mTS molecules. Conformational changes leading to a ligand-induced closing of the active site cleft are observed by comparing the crystal structures of mTS in three different states along the catalytic pathway: ligand-free, dUMP-bound, and dUMP- and Raltitrexed-bound. Possible interaction routes between hydrophobic residues of the mTS protein N-terminal segment and the active site are also discussed.
PDB ID: 4EB4Download
MMDB ID: 99262
PDB Deposition Date: 2012/3/23
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 1.74  Å
Source Organism:
Similar Structures:
Biological Unit for 4EB4: dimeric; determined by author and by software (PISA)
Molecular Components in 4EB4
Label Count Molecule
Proteins (2 molecules)
2
Thymidylate Synthase(Gene symbol: Tyms)
Molecule annotation
Chemicals (14 molecules)
1
2
2
2
3
1
4
7
5
1
6
1
* Click molecule labels to explore molecular sequence information.

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