Life Sciences & Biotechnology
Title : | Structural visualization of distinct binding modalities in selected GPCR-β-arrestin complexes |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Arun K Shukla, Indian Institute Of Technology Kanpur (IITK), Uttar Pradesh |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | arshukla@iitk.ac.in |
Equipments : | Computer work-station for cryo-EM data processing |
Details
Executive Summary : | G protein-coupled receptors (GPCRs), the largest class of cell surface proteins in the human genome, are targets of about one-third of currently prescribed medicines. GPCR-β-arrestin interaction is driven primarily by receptor phosphorylation at Serine and Threonine residues in either their carboxyl-terminus (C-tail) or in the 3rd intracellular loop (ICL3). However, there is a dearth of structural data on β-arrestin interaction for the receptors that engage β-arrestins through their ICL3. The lack of intricate details about the structural and functional differences between the two β-arrestin isoforms (β-arrestin 1 and 2) in GPCR-bound states represents an important knowledge gap in the current conceptual framework. This study aims to visualize the structural details of β-arrestin1/2 engagement with GPCRs through phosphorylated ICL3 using the human muscarinic receptor subtype 2 (M2R) as a model system. The researchers propose reconstituting agonist-M2R-β-arrestin1/2 ternary complexes using a co-expression strategy followed by their structure determination by cryo-EM. The streamlined protocols established here should be adaptable to other GPCR-β-arrestin complexes, facilitating a broad coverage of this important signaling pathway. The structure determination of M2R-β-arrestin complexes as proposed will provide a structural framework to discover G-protein-biased and β-arrestin-biased agonists targeting M2R, potentially facilitating the development of better therapeutics for mental disorders. |
Total Budget (INR): | 79,86,264 |
Organizations involved