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

Abstract:

:Utilizing structure-based design, we have previously demonstrated that it is possible to obtain selective inhibitors of protein-tyrosine phosphatase 1B (PTP1B). A basic nitrogen was introduced into a general PTP inhibitor to form a salt bridge to Asp48 in PTP1B 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 demonstrated that Gly259 in PTP1B forms the bottom of a gateway that allows easy access to the active site for a broad range of substrates, while bulky residues in the same position in other PTPs cause steric hindrance and reduced substrate recognition capacity [Peters, G. H., et al. (2000) J. Biol. Chem. 275, 18201-18209]. The current study was undertaken to investigate the feasibility of structure-based design, utilizing these differences in accessibility to the active site among various PTPs. We show that a general, low-molecular weight PTP inhibitor can be developed into a highly selective inhibitor 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 crystallography, and molecular modeling studies confirmed that selectivity for PTP1B and TC-PTP was achieved due to steric hindrance imposed by bulky position 259 residues in other PTPs.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Iversen LF,Andersen HS,Møller KB,Olsen OH,Peters GH,Branner S,Mortensen SB,Hansen TK,Lau J,Ge Y,Holsworth DD,Newman MJ,Hundahl Møller NP

doi

10.1021/bi011389l

subject

Has Abstract

pub_date

2001-12-11 00:00:00

pages

14812-20

issue

49

eissn

0006-2960

issn

1520-4995

pii

bi011389l

journal_volume

40

pub_type

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