1l8g
From Proteopedia
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| , resolution 2.5Å | |||||||
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| Ligands: | |||||||
| Activity: | Protein-tyrosine-phosphatase, with EC number 3.1.3.48 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of PTP1B complexed with 7-(1,1-Dioxo-1H-benzo[d]isothiazol-3-yloxymethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]
About this Structure
1L8G is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases., Iversen LF, Andersen HS, Moller KB, Olsen OH, Peters GH, Branner S, Mortensen SB, Hansen TK, Lau J, Ge Y, Holsworth DD, Newman MJ, Hundahl Moller NP, Biochemistry. 2001 Dec 11;40(49):14812-20. PMID:11732900
Page seeded by OCA on Thu Mar 20 12:27:46 2008
