1Q6M

THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 3

1Q6M の概要

• エントリーDOI: 10.2210/pdb1q6m/pdb
• 関連するPDBエントリー: 1Q6J 1Q6N 1Q6P 1Q6S 1Q6T
• 分子名称: Protein-tyrosine phosphatase, non-receptor type 1, {[2-(1H-1,2,3-BENZOTRIAZOL-1-YL)-2-(3,4-DIFLUOROPHENYL)PROPANE-1,3-DIYL]BIS[4,1-PHENYLENE(DIFLUOROMETHYLENE)]}BIS(PHOSPHONIC ACID) (3 entities in total)
• 機能のキーワード: phosphatase, secondary binding site, selectivity, 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: 36923.62

構造登録者

Scapin, G.,Patel, S.B.,Becker, J.W.,Wang, Q.,Desponts, C.,Waddleton, D.,Skorey, K.,Cromlish, W.,Bayly, C.,Therien, M.,Gauthier, J.Y.,Li, C.S.,Lau, C.K.,Ramachandran, C.,Kennedy, B.P.,Asante-Appiah, E. (登録日: 2003-08-13, 公開日: 2003-09-30, 最終更新日: 2023-08-16)

主引用文献

Scapin, G.,Patel, S.B.,Becker, J.W.,Wang, Q.,Desponts, C.,Waddleton, D.,Skorey, K.,Cromlish, W.,Bayly, C.,Therien, M.,Gauthier, J.Y.,Li, C.S.,Lau, C.K.,Ramachandran, C.,Kennedy, B.P.,Asante-Appiah, E.
The Structural Basis for the Selectivity of Benzotriazole Inhibitors of Ptp1B
Biochemistry, 42:11451-11459, 2003

PubMed Abstract: Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.

PubMed: 14516196
DOI: 10.1021/bi035098j

実験手法

X-RAY DIFFRACTION (2.2 Å)