1C87

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

1C87 の概要

• エントリーDOI: 10.2210/pdb1c87/pdb
• 関連するPDBエントリー: 1C83 1C84 1C85 1C86 1C88 1ECV
• 分子名称: PROTEIN (PROTEIN-TYROSINE PHOSPHATASE 1B), 2-(OXALYL-AMINO)-4,7-DIHYDRO-5H-THIENO[2,3-C]PYRAN-3-CARBOXYLIC ACID (3 entities in total)
• 機能のキーワード: hydrolase, phosphorylation, ligand, inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P18031
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34991.81

構造登録者

Iversen, L.F.,Andersen, H.S.,Mortensen, S.B.,Moller, N.P. (登録日: 2000-04-16, 公開日: 2000-05-03, 最終更新日: 2023-08-09)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)