1NNY

Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Compound 23 Using a Linked-Fragment Strategy

1NNY の概要

• エントリーDOI: 10.2210/pdb1nny/pdb
• 関連するPDBエントリー: 1NL9 1NO6
• 分子名称: Protein-tyrosine phosphatase, non-receptor type 1, 3-({5-[(N-ACETYL-3-{4-[(CARBOXYCARBONYL)(2-CARBOXYPHENYL)AMINO]-1-NAPHTHYL}-L-ALANYL)AMINO]PENTYL}OXY)-2-NAPHTHOIC ACID (3 entities in total)
• 機能のキーワード: protein tyrosine phosphatase fold, dual-site oxamic acid inhibitor bound to p-loop, hydrolase
• 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: 38085.37

構造登録者

Szczepankiewicz, B.G.,Liu, G.,Hajduk, P.J.,Abad-Zapatero, C.,Pei, Z.,Xin, Z.,Lubben, T.,Trevillyan, J.M.,Stashko, M.A.,Ballaron, S.J.,Liang, H.,Huang, F.,Hutchins, C.W.,Fesik, S.W.,Jirousek, M.R. (登録日: 2003-01-14, 公開日: 2003-04-08, 最終更新日: 2023-08-16)

主引用文献

Szczepankiewicz, B.G.,Liu, G.,Hajduk, P.J.,Abad-Zapatero, C.,Pei, Z.,Xin, Z.,Lubben, T.,Trevillyan, J.M.,Stashko, M.A.,Ballaron, S.J.,Liang, H.,Huang, F.,Hutchins, C.W.,Fesik, S.W.,Jirousek, M.R.
Discovery of a Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Using a Linked-Fragment Strategy
J.Am.Chem.Soc., 125:4087-4096, 2003

PubMed Abstract: Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.

PubMed: 12670229
DOI: 10.1021/ja0296733

実験手法

X-RAY DIFFRACTION (2.4 Å)