Abstract：
:Human thymidylate synthase (hTS), a target for antiproliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer-monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein-protein interactions critical for activity. We computationally identified putative hotspot residues at the interface and designed mutants to perturb the intersubunit interaction. Dimer dissociation constants measured by a FRET-based assay range from 60 nM for wild-type hTS up to about 1 mM for single-point mutants and agree with computational predictions of the effects of these mutations. Mutations that are remote from the active site retain full or partial activity, although the substrate KM values were generally higher and the dimer was less stable. The lower dimer stability of the mutants can facilitate access to the dimer interface by small molecules and thereby aid the design of inhibitors that bind at the dimer interface.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Salo-Ahen OM,Tochowicz A,Pozzi C,Cardinale D,Ferrari S,Boum Y,Mangani S,Stroud RM,Saxena P,Myllykallio H,Costi MP,Ponterini G,Wade RCdoi
10.1021/acs.jmedchem.5b00137subject
Has Abstractpub_date
2015-04-23 00:00:00pages
3572-81issue
8eissn
0022-2623issn
1520-4804journal_volume
58pub_type
杂志文章abstract：:This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase i...
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