Structural Characterizations of Transient and Heterogeneous Protein Complexes

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DESCRIPTION (provided by applicant): Transient and heterogeneous protein interactions play important roles both in the catalytic and regulatory functions of protein complexes and multi-modular machinery. However, the technical challenges involved in structural characterizations of such systems have placed critical barriers against understanding their intrinsic behavior. The vitamin B12-dependent methionine synthase and class Ia ribonucleotide reductases are two enzymes that epitomize such systems where structural insight into their multiple conformations will advance our understanding of their physiological and medically relevant behavior. To meet the technical challenge of investigating these systems, I will exploit the ensemble structural information that can be gained by small- and wide-angle X-ray scattering and employ mathematical methods to deconvolute the mixtures into quantifiable individual states. This work will be complemented by crystallography, spectroscopy, and analytical ultracentrifugation. PUBLIC HEALTH RELEVANCE: Ribonucleotide reductase is a protein found in all organisms that is an important target for cancer drugs, and methionine synthase is an important protein in healthy pregnancies. By investigating the structure of these "floppy" proteins that have been challenging to study, we will gain better insight into drug design targeting ribonucleotide reductase and genetic mutations in methionine synthase.