期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 143, 期 10, 页码 3830-3845出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c11806
关键词
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资金
- Carl Tryggers Foundation for Scientific Research [CTS 19:172]
- Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellowship) [2018.0140]
- Human Frontier Science Program [RGP0041/2017]
- Swedish Research Council [2019-03499]
- BBSRC [BB/M026280/1]
- Swedish National Infrastructure for Computing [SNIC 2018/2-3, 2019/2-1, 2019/3-258, 2020/5-250]
- BBSRC [BB/M026280/1] Funding Source: UKRI
- Swedish Research Council [2019-03499] Funding Source: Swedish Research Council
This study investigates the link between the dynamics of the WPD-loop and catalysis rates in human protein tyrosine phosphatase 1B (PTP1B) and YopH from Yersinia pestis. Computational simulations reveal key residues and structural features responsible for differences in loop dynamics, as well as pathways for allosteric communication in these enzymes. The findings shed light on how PTP enzymes in the family may adapt to environmental changes and regulate their catalytic activities.
Protein tyrosine phosphatases (PTPs) play an important role in cellular signaling and have been implicated in human cancers, diabetes, and obesity. Despite shared catalytic mechanisms and transition states for the chemical steps of catalysis, catalytic rates within the PTP family vary over several orders of magnitude. These rate differences have been implied to arise from differing conformational dynamics of the closure of a protein loop, the WPD-Ioop, which carries a catalytically critical residue. The present work reports computational studies of the human protein tyrosine phosphatase 1B (PTP1B) and YopH from Yersinia pestis, for which NMR has demonstrated a link between their respective rates of WPD-Ioop motion and catalysis rates, which differ by an order of magnitude. We have performed detailed structural analysis, both conventional and enhanced sampling simulations of their loop dynamics, as well as empirical valence bond simulations of the chemical step of catalysis. These analyses revealed the key residues and structural features responsible for these differences, as well as the residues and pathways that facilitate allosteric communication in these enzymes. Curiously, our wild-type YopH simulations also identify a catalytically incompetent hyper-open conformation of its WPD-loop, sampled as a rare event, previously only experimentally observed in YopH-based chimeras. The effect of differences within the WPD-loop and its neighboring loops on the modulation of loop dynamics, as revealed in this work, may provide a facile means for the family of PTP enzymes to respond to environmental changes and regulate their catalytic activities.
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