1C86

CRYSTAL STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE 1B (R47V,D48N) COMPLEXED WITH 2-(OXALYL-AMINO-4,7-DIHYDRO-5H-THIENO[2,3-C]PYRAN-3-CARBOXYLIC ACID

Summary for 1C86

• Entry DOI: 10.2210/pdb1c86/pdb
• Related: 1C83 1C84 1C85 1C87 1C88 1ECV
• Descriptor: PROTEIN (PROTEIN-TYROSINE PHOSPHATASE 1B), 2-(OXALYL-AMINO)-4,7-DIHYDRO-5H-THIENO[2,3-C]PYRAN-3-CARBOXYLIC ACID (3 entities in total)
• Functional Keywords: hydrolase, phosphorylation, ligand, inhibitor
• 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: 34932.77

Authors

Iversen, L.F.,Andersen, H.S.,Mortensen, S.B.,Moller, N.P. (deposition date: 2000-04-16, release date: 2000-05-03, Last modification date: 2023-08-09)

Primary citation

Iversen, L.F.,Andersen, H.S.,Branner, S.,Mortensen, S.B.,Peters, G.H.,Norris, K.,Olsen, O.H.,Jeppesen, C.B.,Lundt, B.F.,Ripka, W.,Moller, K.B.,Moller, N.P.
Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B.
J.Biol.Chem., 275:10300-10307, 2000

PubMed Abstract: Several protein-tyrosine phosphatases (PTPs) have been proposed to act as negative regulators of insulin signaling. Recent studies have shown increased insulin sensitivity and resistance to obesity in PTP1B knockout mice, thus pointing to this enzyme as a potential drug target in diabetes. Structure-based design, guided by PTP mutants and x-ray protein crystallography, was used to optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor (2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inhibitor. This was achieved by addressing residue 48 as a selectivity determining residue. By introducing a basic nitrogen in the core structure of the inhibitor, a salt bridge was formed to Asp-48 in PTP1B. In contrast, the basic nitrogen causes repulsion in other PTPs containing an asparagine in the equivalent position resulting in a remarkable selectivity for PTP1B. Importantly, this was accomplished while retaining the molecular weight of the inhibitor below 300 g/mol.

PubMed: 10744717
DOI: 10.1074/jbc.275.14.10300

Experimental method

X-RAY DIFFRACTION (2.3 Å)