Structural Basis for the Inhibition Mechanism of HUman CSE and a study on c-CBL complexes

Abstract

Dysregulation of hydrogen sulfide (H2S), an endogenous gasotransmitter, is associated with various diseases such as hypertension, diabetes mellitus, septic or haemorrhagic shock and pancreatitis. Cystathionine-¿-lyase is the main H2S producing enzyme in the cardiovascular system and is responsible for the above mentioned diseases. Here we report several different crystal structure forms/complexes of human Cystathionine-¿-lyase and relevant biophysical, biochemical studies. This study provides new insights into the inhibition mechanism of production of H2S and insights which will facilitate the structure-based design of novel inhibitors/activators of human Cystathionine-¿-lyase for therapeutic purposes. c-Cbl is an E3 ubiquitin ligase and multi-functional protein that plays a vital role in controlling cell phenotype. Using Surface Plasmon Resonance, we found that multiple phosphorylation in c-Cbl recruiting motif of EGFR and Sprouty2 significantly reduces their binding affinity towards c-Cbl TKB domain. However, the crystal structure displays minimal binding pattern changes. Please refer to the thesis for detailed discussion.