Sandra B. Gabelli
PI3Ka and their downstream effectors: the crossroad of cancer, diabetes and inflammation.
The project aims to understand the molecular and structural mechanism of activation and inhibition of class I phosphoinositide 3 kinases. These lipid kinases are the key signaling element in a diverse array of cellular functions such as cell growth, motility, and, and a validated targets for pharmacological intervention. Deregulation of PI3K pathway is implicated in a variety of diseases including thromboembolism, inflammation, autoimmune diseases and cancer. We determined the structure of PI3Ka in heterodimeric form showing all five domains of p110a in complex with the nSH2 and iSH2 domains of the p85a. We determined the structure of the somatic p110a H1047R/niSH2 mutant alone and in complex with the inhibitor wortmannin. The PI3K enzyme, as the hub of the PI3K/AKT/ mTOR pathway, presents an opportunity where structural biology, enzymology, and inhibitor design converge to both elucidate mechanisms of action and provide initial hits for targeted therapies.
Isoprenoid Pathway as a target of protozoan parasitic diseases.
Bisphosphonates, drugs used to treat bone resorption, have been shown to have antiparasitic effect. In humans, they act by targeting the farnesyl disphosphate synthase lowering the levels of protein prenylation. Our work is focused in tailoring nitrogen-containing bisphosphonates to the parasitic enzymes minimizing their effect in the host. We are using mutational analysis, enzymatic assays, isothermal calorimetry and X-ray crystallography studies to give the structural basis of specificity of the compounds.
Nudix Hydrolases: Structure to Function.
Nudix hydrolases are a superfamily of pyrophosphatases catalyzing the hydrolysis of a nucleoside diphosphate linked to another moiety. Some of the substrates are metabolites that require modulation during the cell cycle or periods of stress. Others are deleterious compounds that must be eliminated. Most of the Nudix hydrolases are “house cleaning enzymes” that control the level of these compounds. The enzymes and proteins are characterized by the signature sequence (GX5EX7REUXEEXGU where U is I, L, or V); this sequence forms the catalytic site for the metal required in the reaction. Our work attempts to define the basis for identifying families according to their catalytic activity, tertiary structure, quaternary arrangement and phenotype. Using a battery of kinetic, biochemical, genetic studies we have defined the ADPR-ase, GDPMH-ase, DHNTP-ase, RppHase, Co-Ase, CDPChase families.
Development of Interactive Modules for Medical Education
Interactive modules that correlate a topic of choice in the scientific foundation of medicine with its physiology are being develop as a tool to reinforce molecular knowledge linked to their physiological relevance.