Open AccessAlanine Mutants of the Interface Residues of Human Thymidylate Synthase Decode Key Features of the Binding Mode of Allosteric Anticancer Peptides
Author(s) -
A. Tochowicz,
Matteo Santucci,
Puneet Saxena,
Giambattista Guaitoli,
Matteo Trande,
J. Finer-Moore,
Robert M. Stroud,
Maria Paola Costi
Publication year - 2014
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm5011176
Subject(s) - allosteric regulation , thymidylate synthase , chemistry , alanine , peptide , alanine scanning , biochemistry , binding site , stereochemistry , mutant , enzyme , amino acid , mutagenesis , cancer , gene , medicine , fluorouracil
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.