Md. Sazzad Khan, Mohamad Aman Jairajpuri
Protein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia University, New-Delhi-110025, India.
Identifying the molecular basis of protein aggregation mechanism and devising its cure is an exciting area of protein chemistry. Serine Protease Inhibitor (serpin) family share a common secondary folds and follows a common mechanism of inhibition. The family is characterized by more than 30% sequence homology and a common framework tertiary structure. Members of serpin play an important role in regulation of enzyme involved in proteolytic cascades. Mutation in serpins can lead directly to functional defects or polymer formation that can compromise the specific function and leads protein aggregation and accumulation of polymers that can cause cell toxicity and death. Polymerizations of serpins is associated with diseases like emphysema/cirrhosis, angioedema, familial dementia, chronic obstructive bronchitis and thrombosis. Serpin polymerization can be attributed to an inherent flexibility and metastability of the native serpin fold. In this conformation the conversion to lower energy fold is satisfied by the formation of intermolecular contact instead of intra molecular ones, which lead to the polymerization and which is the basis of great majority of all serpin related disorders or serpinopathies. Few studies have shown that chemical chaperones can reverse polymerization however, the effect of these compound on cofactor binding, stability, conformational change and inhibition of serpin continues to remain largely unknown. We have screened a number of chemical chaperones that can retard antithrombin polymerization on native gel. Some of these amino acid based chemical chaperone were shown to reduce polymerization at physiological condition. A mixed chaperone based strategy shows a reduction in concentration of chemical chaperone at which it hinders polymerization. Circular dichorism and flurometric data shows that these leads compound can modulate antithrombin structure. Reduction in the high molecular weight polymer band in antithrombin was also shown to coincide with increased inhibition of thrombin in presence of chemical chaperone but not in its absence. Using Autodock software we also show that these lead chemical chaperones can bind appreciably with serpin. The result identifies several lead compounds and shows that chemical chaperone will be effective in attenuating the serpin conformation diseases and offer a possible therapeutic potential.Read more…