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You are here: Home Administration Chemistry & Biochemistry Department Events 2018 October Biochemistry Seminar: Patrick Loria, "Micro-millisecond motions in enzyme function and allostery"

Biochemistry Seminar: Patrick Loria, "Micro-millisecond motions in enzyme function and allostery"

Patrick Loria, Professor of Chemistry, Professor of Molecular Biophysics, Yale University, CT, "Micro-millisecond motions in enzyme function and allostery"
When Oct 17, 2018
from 12:00 PM to 01:00 PM
Where CUNY ASRC Main Auditorium
Contact Name
Contact Phone 212-650-8803
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Protein tyrosine phosphatases are critical enzymes that regulate numerous metabolic pathways. Specifically, PTP1B and VHR are signal transduction modulators for insulin and leptin and extracellular signaling and c-Jun N-terminal kinases, respectively. The catalytic function of these enzymes is initiated by the closure of the active site acid loop upon substrate binding, where a critical aspartic acid in the catalytic loop drives the cleavage and hydrolysis of the phosphotyrosine substrate to yield the dephosphorylated product. We probed the conformational equilibrium landscape of the catalytic loops in PTP1B and VHR by characterizing a series of alanine point mutations along the loop sequence with NMR spectroscopy, X-ray crystallography, steady-state, and transient kinetic analysis. In a series of 2D NMR spectra of these mutants, we identified residues comprising a novel allosteric network whose chemical shifts align in a linear manner on a trajectory tracking an open (apo) – to – closed (substrate bound) acid-loop transition. Crystal structures of these mutants in the apo form demonstrate a range of loop conformations ranging from open, to 50% closure to 100% closure. These data suggest that modifying the flexibility of the catalytic loop alters the conformational equilibrium landscape of the phosphatases locally (at the loop) and globally. Additionally, our kinetic studies of the dephosphorylation reaction for the acid-loop mutants found that the loop conformational equilibrium and rate of catalysis are highly correlated. This suggests that the rate of catalysis in tyrosine phosphatases is governed by the kinetics of acid-loop closure. These results provide insight into the evolutionary differences between structural homologues of tyrosine phosphatases, and how acid-loop primary sequence and backbone flexibility can affect global structure and function.

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