9CYP

Crystal structure of I19V mutant human PTP1B (PTPN1) at room temperature (298 K)

9CYP の概要

• エントリーDOI: 10.2210/pdb9cyp/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 1, MAGNESIUM ION (3 entities in total)
• 機能のキーワード: ptp1b, phosphatase, allostery, ptp, hydrolase
• 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: 37452.04

構造登録者

Ebrahim, A.,Perdikari, A.,Woods, V.A.,Lawler, K.,Bounds, R.,Shah, D.S.,Singh, N.I.,Mehlman, T.,Riley, B.T.,Sharma, S.,Morris, J.W.,Keogh, J.M.,Henning, E.,Smith, M.,Farooqi, I.S.,Keedy, D.A. (登録日: 2024-08-02, 公開日: 2024-08-21, 最終更新日: 2025-12-10)

主引用文献

Perdikari, A.,Woods, V.A.,Ebrahim, A.,Lawler, K.,Bounds, R.,Shah, D.S.,Singh, N.I.,Mehlman, T.S.,Riley, B.T.,Sharma, S.,Morris, J.W.,Keogh, J.M.,Henning, E.,Smith, M.,Farooqi, I.S.,Keedy, D.A.
Structures of human protein tyrosine phosphatase variants reveal targetable allosteric sites.
J.Biol.Chem., 301:110852-110852, 2025

PubMed Abstract: Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin signaling whose disruption protects against diet-induced obesity in mice. We investigated whether structural characterization of human PTP1B variant proteins might reveal allosteric sites to target for weight loss therapy. To do so, we selected 12 rare variants for functional characterization from exomes from 997 people with persistent thinness and 200,000 people from the UK Biobank. Seven of 12 variants impaired PTP1B function by increasing leptin-stimulated signal transducer and activator of transcription 3 phosphorylation in human cells. Focusing on the variants in and near the ordered catalytic domain, we ascribed structural mechanisms to their functional effects using in vitro enzyme activity assays, room-temperature X-ray crystallography, and local hydrogen-deuterium exchange mass spectrometry. By combining these complementary structural biology experiments for multiple variants, we characterize an inherent allosteric network in PTP1B that differs from previously reported allosteric inhibitor-driven mechanisms mediated by catalytic loop motions. The most functionally impactful variant sites map to highly ligandable surface sites, suggesting untapped opportunities for allosteric drug design. Overall, these studies can inform the targeted design of allosteric PTP1B inhibitors for the treatment of obesity.

PubMed: 41135676
DOI: 10.1016/j.jbc.2025.110852

実験手法

X-RAY DIFFRACTION (1.99 Å)