7KLX

Protein Tyrosine Phosphatase 1B with inhibitor

7KLX の概要

• エントリーDOI: 10.2210/pdb7klx/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 1, 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-hydroxybenzoic acid, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: insulin, regulation, hydrolase/hydrolase inhibitor, hydrolase-hydrolase inhibitor complex
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33058.13

構造登録者

Battaile, K.P.,Chirgadze, Y.,Ruzanov, M.,Romanov, V.,Lam, K.,Gordon, R.,Lin, A.,Lam, R.,Pai, E.,Chirgadze, N. (登録日: 2020-11-01, 公開日: 2022-01-19, 最終更新日: 2023-10-18)

主引用文献

Chirgadze, Y.N.,Battaile, K.P.,Likhachev, I.V.,Balabaev, N.K.,Gordon, R.D.,Romanov, V.,Lin, A.,Karisch, R.,Lam, R.,Ruzanov, M.,Brazhnikov, E.V.,Pai, E.F.,Neel, B.G.,Chirgadze, N.Y.
Signal transfer in human protein tyrosine phosphatase PTP1B from allosteric inhibitor P00058.
J.Biomol.Struct.Dyn., :1-10, 2021

PubMed Abstract: Protein tyrosine phosphatases constitute a family of cytosolic and receptor-like signal transducing enzymes that catalyze the hydrolysis of phospho-tyrosine residues of phosphorylated proteins. PTP1B, encoded by , is a key negative regulator of insulin and leptin receptor signaling, linking it to two widespread diseases: type 2 diabetes mellitus and obesity. Here, we present crystal structures of the PTP1B apo-enzyme and a complex with a newly identified allosteric inhibitor, 2-(2,5-dimethyl-pyrrol-1-yl)-5-hydroxy-benzoic acid, designated as P00058. The inhibitor binding site is located about 18 Å away from the active center. However, the inhibitor causes significant re-arrangements in the active center of enzyme: residues 45-50 of catalytic Tyr-loop are shifted at their Cα-atom positions by 2.6 to 5.8 Å. We have identified an event of allosteric signal transfer from the inhibitor to the catalytic area using molecular dynamic simulation. Analyzing change of complex structure along the fluctuation trajectory we have found the large Cα-atom shifts in external strand, residues 25-40, which occur at the same time with the shifts in adjacent catalytic p-Tyr-loop. Coming of the signal to this loop arises due to dynamic fluctuation of protein structure at about 4.0 nanoseconds after the inhibitor takes up its space. Communicated by Ramaswamy H. Sarma.

PubMed: 34705594
DOI: 10.1080/07391102.2021.1994879

実験手法

X-RAY DIFFRACTION (1.839 Å)