Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases

Citation
Lf. Iversen et al., Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases, BIOCHEM, 40(49), 2001, pp. 14812-14820
Citations number
42
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHEMISTRY
ISSN journal
00062960 → ACNP
Volume
40
Issue
49
Year of publication
2001
Pages
14812 - 14820
Database
ISI
SICI code
0006-2960(200112)40:49<14812:SHAABF>2.0.ZU;2-8
Abstract
Utilizing structure-based design, we have previously demonstrated that it i s possible to obtain selective inhibitors of protein-tyrosine phosphatase 1 B (PTPIB). A basic nitrogen was introduced into a general PTP inhibitor to form a salt bridge to Asp48 in PTPIB and simultaneously cause repulsion in PTPs containing an asparagine in the equivalent position [Iversen, L.F., et al. (2000) J. Biol. Chem. 275, 10300-10307]. Further, we have recently dem onstrated that Gly259 in PTP1B forms the bottom of a gateway that allows ea sy access to the active site for a broad range of substrates, while bulky r esidues in the same position in other PTPs cause steric hindrance and reduc ed substrate recognition capacity [Peters, G.H., et al. (2000) J. Biol. Che m. 275, 18201-18209]. The current study was undertaken to investigate the f easibility of structure-based design, utilizing these differences in access ibility to the active site among various PTPs. We show that a general, low- molecular weight PTP inhibitor can be developed into a highly selective inh ibitor for PTP1B and TC-PTP by introducing a substituent, which is designed to address the region around residues 258 and 259. Detailed enzyme kinetic analysis with a set of wild-type and mutant PTPs, X-ray protein crystallog raphy, and molecular modeling, studies confirmed that selectivity for PTPIB and TC-PTP was achieved due to steric hindrance imposed by bulky position 259 residues in other PTPs.