Biochemistry Seminar: Daniel Keedy, Mapping and Exploiting the Internal Wiring of Dynamic Protein Structures

Wed, May 05, 2021 - 12:00 PM — Wed, May 05, 2021 - 01:00 PM
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Daniel Keedy, Assistant Professor, Dept of Chemistry & Biochemistry, CCNY, CUNY ASRC, will give a talk on "Mapping and Exploiting the Internal Wiring of Dynamic Protein Structures"


The Keedy lab aims to elucidate the conformational ensembles of proteins and understand how they are modulated by ligands, mutations, and other perturbations to control function.  We are particularly interested in how such ensembles relate to allostery, in which transitions between conformations relay intramolecular signals from one site to another within a protein.  However, traditional methods in structural biology are limited in their ability to reveal the specific conformations and transitions that occur during allostery.  We are working to overcome this hurdle by exploiting the untapped potential of multidataset X-ray crystallography methods, including multitemperature diffraction, high-throughput crystallographic small-molecule fragment screens, and multiconformer modeling algorithms.  These new approaches are particularly relevant to elucidating allosteric regulatory mechanisms in human Protein Tyrosine Phosphatases (PTPs).  Different PTPs play distinct, critical roles in various cellular processes and disease states, yet PTPs remain relatively poorly understood.  Our work seeks to answer fundamental questions about these biomedically critical enzymes:  How do conformational motions underlying allostery differ between PTPs?  How is allosteric rewiring achieved within a common protein architecture?  And can new allosteric sites be targeted for specific inhibition of individual PTPs? Overall, our research aims to provide fresh insights into the underlying mechanisms of allostery in PTPs and other proteins, and to pave the way toward development of potent, specific allosteric modulators for individual PTPs for both basic science and therapeutic interventions.

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