Alanine mutants of the interface residues of human thymidylate synthase decode key features of the binding mode of allosteric anticancer peptides

J Med Chem. 2015 Jan 22;58(2):1012-8. doi: 10.1021/jm5011176. Epub 2014 Dec 29.

Abstract

Allosteric peptide inhibitors of thymidylate synthase (hTS) bind to the dimer interface and stabilize the inactive form of the protein. Four interface residues were mutated to alanine, and interaction studies were employed to decode the key role of these residues in the peptide molecular recognition. This led to the identification of three crucial interface residues F59, L198, and Y202 that impart activity to the peptide inhibitors and suggest the binding area for further inhibitor design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine
  • Allosteric Regulation
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mutagenesis, Site-Directed
  • Structure-Activity Relationship
  • Thymidylate Synthase / antagonists & inhibitors*
  • Thymidylate Synthase / chemistry
  • Thymidylate Synthase / genetics

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Thymidylate Synthase
  • Alanine

Associated data

  • PDB/4FGT