1L8G

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

Summary for 1L8G

• Entry DOI: 10.2210/pdb1l8g/pdb
• Related: 1c83
• Descriptor: PROTEIN-TYROSINE PHOSPHATASE, NON-RECEPTOR TYPE 1, 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 (3 entities in total)
• Functional Keywords: protein-inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side: P18031
• Total number of polymer chains: 1
• Total formula weight: 37832.08

Authors

Iversen, L.F.,Andersen, H.S.,Moller, K.B.,Olsen, O.H.,Peters, G.H.,Branner, S.,Mortensen, S.B.,Hansen, T.K.,Lau, J.,Ge, Y.,Holsworth, D.D.,Newman, M.J.,Moller, N.P.H. (deposition date: 2002-03-20, release date: 2002-05-08, Last modification date: 2024-02-14)

Primary citation

Iversen, L.F.,Andersen, H.S.,Moller, K.B.,Olsen, O.H.,Peters, G.H.,Branner, S.,Mortensen, S.B.,Hansen, T.K.,Lau, J.,Ge, Y.,Holsworth, D.D.,Newman, M.J.,Hundahl Moller, N.P.
Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases.
Biochemistry, 40:14812-14820, 2001

PubMed 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.

PubMed: 11732900
DOI: 10.1021/bi011389l

Experimental method

X-RAY DIFFRACTION (2.5 Å)