Related Experiment Videos
Thymidylate synthase: structure, inhibition, and strained conformations during catalysis
1Department of Biochemistry, University of Arizona, Tucson 85721, USA.
Pharmacology & Therapeutics
|April 16, 1998
Summary
Thymidylate synthase (TS) is a key target in cancer therapy. Recent structural studies reveal how ligand-induced conformational changes in TS are crucial for its catalytic mechanism and inhibition by antifolates.
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Thymidylate synthase (TS) is essential for DNA synthesis and a validated target for chemotherapy.
- Understanding TS mechanism and inhibition is critical for developing effective anticancer drugs.
Purpose of the Study:
- To elucidate the role of conformational changes in thymidylate synthase (TS) catalysis and inhibition.
- To provide insights into the mechanism of action for novel antifolates.
Main Methods:
- X-ray crystallography to determine structures of TS complexes with substrates, cofactors, and inhibitors.
- Mechanistic studies to analyze enzyme activity and ligand interactions.
Main Results:
- Ligand-induced conformational changes in TS are vital for catalysis, stabilizing reactive intermediates and cofactor conformers.
- The most effective TS inhibitors induce and stabilize specific conformational changes, such as BW1843 distorting the active site.
- Crystal structures of TS bound to dUMP, CH2THF, nucleotide analogs, and antifolates (BW1843, ZD1694, AG337) were determined.
Conclusions:
- Conformational flexibility of TS is integral to its catalytic function and susceptibility to inhibition.
- Structure-based drug design of antifolates targeting TS conformational states holds promise for cancer treatment.