Seminar Title: “Protein conformational change we can believe in!”
James Fraser, Associate Professor of Bioengineering and Therapeutic Science, UCSF School of Pharmacy
ABSTRACT: Protein conformational landscapes are complex and predicting the conformational response to physiologically relevant perturbations like mutation or small molecule binding is a major challenge. Often, functionally-relevant states are nearly isoenergetic (separated in energy by a few kT, or less), meaning that at physiological temperatures, multiple conformational states populate the ensemble. Using newly developed multiconformer models of X-ray crystallography data, we have shown how population shifts can result from simple temperature perturbation. Our experience over multiple systems has demonstrated that temperature sensitive conformational states are the same ones used by evolution to create new functions, by small molecules in creating new binding sites, and by enzymes to transit through a catalytic cycle. Using an easily controllable physical perturbation (temperature) to predict the conformational response to physiological perturbations suggests the specific conformations to enforce at allosteric sites to achieve long-range control over protein activity.
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