Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases

Rory M Crean, Marc W Van Der Kamp, Shina Caroline Lynn Kamerlin*, et al.

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

30 Citations (Scopus)
51 Downloads (Pure)


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-loop, 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-loop 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.
Original languageEnglish
Pages (from-to)3830-3845
Number of pages16
JournalJournal of the American Chemical Society
Issue number10
Early online date4 Mar 2021
Publication statusPublished - 17 Mar 2021

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© 2021 The Authors. Published by American Chemical Society.


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