UCSF

All functions of a protein involve its physical interactions, however transient, with specific other molecules (ligands), large or small. Protein structure and its dynamics, determined by sequence, in turn determine which molecules are able to bind to the protein. Druggable proteins are defined as those whose function can be modulated with a small molecule. The contents of this dissertation focus on leveraging the knowledge about protein structure and changes in protein structure to identify small molecule modulators of protein function, thus expanding the druggable proteome. The studied proteins include members of the kinase and SLC transporter superfamilies, both important drug targets. First, we separately examine the impact of mutations on the structures of two kinases, FLT3 and BCR-ABL, and the resistance of these mutants to drugs. We provide a structure-based rationale for the cause of resistance and offer treatment alternatives. Second, we address the modulation of function of human organic cation transporters (OCTs), either through phosphorylation or structure-guided screens to discover novel small molecule inhibitors of these transporters. We establish that by combining docking and in vitro high-throughput screens, competitive and non-competitive ligands of OCTs can be predicted accurately. Third, we examine the quaternary structure of the human concentrative nucleoside transporters (CNTs) to gain new insight into their functions and use structure-guided screens to discover novel ligands to modulate them. We show that human concentrative nucleoside transporter 3 forms homo-oligomers, thus encouraging efforts on finding allosteric inhibitors. Finally, we present a large-scale study of the impact of cancer mutations on protein structure, with the hope of expanding the druggable proteome through the discovery of mutant-specific binding pockets that would allow for selective, functional inhibition or activation.