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.
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