Daniel Keedy, Assistant Professor, Department of Chemistry & Biochemistry, City College of New York, and CUNY ASRC Structural Biology Initiative, New York, will be giving a seminar titled, "Mapping and Exploiting the Internal Wiring of Dynamic Protein Structures."

Zoom link: https://gc-cuny.zoom.us/j/91637964386. Meeting ID:  916 3796 4386. Passcode: asrc+ccny

ABSTRACT

Protein function hinges on dynamic shifts of tertiary structure, but it remains challenging to map protein conformational landscapes at high resolution using traditional approaches in structural biology. Our lab leverages avant-garde computational and experimental methods to illuminate protein structural excursions to excited states, and explores their fundamental connections to biological functions including ligand binding, enzyme catalysis, and allostery. First, for the archetypal protein tyrosine phosphatase (PTP), PTP1B, we report the largest crystallographic ligand screen to date for any protein at room temperature, in contrast to >94% of protein-ligand crystal structures which were solved at cryogenic temperature. This trove of structural data reveals that temperature modulates ligand binding pose, solvation, location, and allosteric protein response. Having shown that temperature modulates protein and ligand conformational ensembles, we next sought to contrast its effects to those of a complementary biophysical perturbation that has been under-explored by crystallography: pressure. Using a relative of PTP1B, the idiosyncratic PTP STEP, we quantitatively explored the temperature and pressure axes with respect to protein structure. Our results reveal that high temperature vs. high pressure have different effects on global unit cell and protein volumes, ordered solvation patterns, and protein conformational ensembles, with each perturbation stabilizing distinct aspects of active-like STEP states. Overall, our lab’s research highlights the importance of moving beyond the single-structure paradigm to build a more fundamental understanding of dynamic protein function.