Life Sciences & Biotechnology
Title : | Computer Simulation Studies on the pH Dependent Structure and Dynamics of Carbonic Anhydrase IX |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Biophysics |
Principal Investigator : | Dr. Srabani Taraphder, Indian Institute Of Technology (IIT) Kharagpur, West Bengal |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | srabani@chem.iitkgp.ac.in |
Equipments : | Computational network storage server |
Details
Executive Summary : | The human carbonic anhydrase (HCA) enzyme, HCA II and IX, have been identified as potential drug targets. HCA II is monomeric and found in the cytosol of cells, while HCA IX is a transmembrane, dimeric glycoprotein with four domains in each monomer unit. High HCA IX expression is linked to hypoxia-associated tumor acidosis and metastatic phenotype. It helps maintain low intracellular pH and adapts cancer cells to toxic conditions. Recent literature focuses on isozyme-specific inhibition of HCA IX by novel molecules at nano-to sub-nano-molar concentrations. However, only the catalytic domain of HCA IX has been crystallized, and the catalytic mechanism of this isozyme is mostly unexplored. This project aims to conduct the first-ever computer simulation study on the functionally important conformational dynamics of wild type HCA IX in the absence of any inhibitor. The first part involves generating a reliable starting model of the membrane-embedded multi-domain structure of the dimeric enzyme, including a unique disordered proteoglycan (PG)-like domain, catalytic (CA) domain, transmembrane (TM) segment, and intra-cytoplasmic (IC) portion. The second part probes the pH-dependent structure and dynamics of HCA IX in water, identifying important conformational transitions and reorganization of internal water molecules. The results from the first part are expected to provide the first quantitative model structure of HCA IX, while the second part will provide a molecular understanding of why HCA IX is stable at low extra-cellular pH for cancer cells. |
Total Budget (INR): | 36,38,096 |
Organizations involved