7L0H

Vanadate-bound PTP1B T177G

7L0H の概要

• エントリーDOI: 10.2210/pdb7l0h/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 1, VANADATE ION (3 entities in total)
• 機能のキーワード: protein tyrosine phosphatase, 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: 37410.49

構造登録者

Shen, R.D.,Hengge, A.C.,Johnson, S.J. (登録日: 2020-12-11, 公開日: 2021-05-12, 最終更新日: 2023-10-18)

主引用文献

Shen, R.,Crean, R.M.,Johnson, S.J.,Kamerlin, S.C.L.,Hengge, A.C.
Single Residue on the WPD-Loop Affects the pH Dependency of Catalysis in Protein Tyrosine Phosphatases.
Jacs Au, 1:646-659, 2021

PubMed Abstract: Catalysis by protein tyrosine phosphatases (PTPs) relies on the motion of a flexible protein loop (the WPD-loop) that carries a residue acting as a general acid/base catalyst during the PTP-catalyzed reaction. The orthogonal substitutions of a noncatalytic residue in the WPD-loops of YopH and PTP1B result in shifted pH-rate profiles from an altered kinetic p of the nucleophilic cysteine. Compared to wild type, the G352T YopH variant has a broadened pH-rate profile, similar activity at optimal pH, but significantly higher activity at low pH. Changes in the corresponding PTP1B T177G variant are more modest and in the opposite direction, with a narrowed pH profile and less activity in the most acidic range. Crystal structures of the variants show no structural perturbations but suggest an increased preference for the WPD-loop-closed conformation. Computational analysis confirms a shift in loop conformational equilibrium in favor of the closed conformation, arising from a combination of increased stability of the closed state and destabilization of the loop-open state. Simulations identify the origins of this population shift, revealing differences in the flexibility of the WPD-loop and neighboring regions. Our results demonstrate that changes to the pH dependency of catalysis by PTPs can result from small changes in amino acid composition in their WPD-loops affecting only loop dynamics and conformational equilibrium. The perturbation of kinetic p values of catalytic residues by nonchemical processes affords a means for nature to alter an enzyme's pH dependency by a less disruptive path than altering electrostatic networks around catalytic residues themselves.

PubMed: 34308419
DOI: 10.1021/jacsau.1c00054

実験手法

X-RAY DIFFRACTION (2.1 Å)