Dr. Soumendra Rana

Dr. Soumendra Rana |Clyto Access

School of Basic Sciences, IIT Bhubaneswar, India

Speaker

Expertise: The structure function relationship in peptide and protein binding G-protein Coupled Receptors (GPCR).

Bio:

Dr. Soumendra Rana is currently an Assistant Professor (Chemistry and Biosciences since 2013) at the School of Basic Sciences, Indian Institute of Technology Bhubaneswar, India. He received his PhD (2007) in broad area of Molecular Biophysics from Indian Institute of Technology Bombay (India), followed by post-doctoral training, respectively from University of Arizona, Tucson (USA), Washington University School of Medicine in Saint Louis (USA), and Saint Louis University School of Medicine (USA).His laboratory aims to devise methods and molecules (organic and bio-organic) for selective targeting of GPCRs in tissues for potential discovery of therapeutic leads, by recruiting a chemical biology approach, comprising a variety of computational biology, molecular biophysics and molecular biology techniques. He is also associated with several open access journals and routinely publishes in reputed international journals, including presentations in both national and international conferences.

Presentation :

Title : Molecular Insights into Pharmacology and Signaling of hC5a Receptor for Potential Drug Discovery

Abstract :

The anaphylatoxin receptor C5aR is one of the two major G-protein coupled receptors (GPCRs), including the C5L2 receptor, known in the human genome that interact with the complement component fragment 5a (hC5a),the most potent proinflammatory polypeptide generated as the proteolytic byproduct of complement component 5 (C5) during the activation of the complement cascade. The interaction is known to trigger diverse non-immunological and immunological responses in several tissues and thus have been tagged “druggable” by the pharma-majors for discovery of potential therapeutics. However, lack of an experimental structure of C5aR have greatly hindered the prospective development of targeted therapeutics, including the rational optimization of the known lead molecules as potential drugs.Nevertheless, biochemical studies have hypothesized a “two-site” binding interaction between the hC5a that recruits the “site1” in the N-terminus and “site2” in the extracellular surface (ECS) of the C5aR, though the precise molecular interactionsare yet to be realized at atomistic resolution. In our quest toward understanding the pharmacology of hC5a-C5aR interaction better, we have recently generated the first set of atomistic model structures of C5aR both in free and in complex with several agonist, inverse agonist and antagonists, demonstrating the plausible “orthosteric” site2 at the ECS of C5aR. In addition, we have also recently hypothesized that hC5a can be allosteric and thus have identified a pair of “allosteric switches” on hC5a that potentially modulate the C5aR signaling and most likely harbor the hot spot residues for interactions with the “site1” of C5aR. Utilizing the knowledge, we have further generated the model complexes of C5aR bound to the native agonist hC5a and an engineered antagonist A8 derived from hC5a.Interestingly, the model complexes illustrate the “two-site” binding at an atomistic resolution for the first time in excellent agreement with independently reported binding and signaling studies.Moreover, we have now generated the “molecular complex” of hC5a-C5aR-G protein. This significant development has helped us to identify promising drug like molecules as “neutraligands”, which can potentially neutralize the function of hC5a by binding to the hot spots, as observed in case of targeted antibodies. In the absence of an experimental structure of C5aR, our model structures provide mechanistic insights into the activation of C5aR and thus emerge asa promising platform for design and discovery of potential leads, optimizable as future drugs, targeting the hC5a-C5aR signaling axes.

Related Journals & Conferences :

International Biotechnology and Pharmaceutical Industry Forum