Bachelor of Science, Stella Maris College (2005)
Doctor of Philosophy, University Of Sydney (2012)
Master of Science, Sri Ramachandra Medical Colleg (2008)
Brian Kobilka, Postdoctoral Faculty Sponsor
Conformational transitions of a neurotensin receptor1-Gi1complex.
Neurotensin receptor1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple subtypes of G protein, and is involved in the regulation of blood pressure, body temperature, weight and the response to pain. Here we present structures of human NTSR1 in complex with the agonist JMV449 and the heterotrimeric Gi1 protein, at a resolution of 3A. We identify two conformations: a canonical-state complex that is similar to recently reported GPCR-Gi/o complexes (in which the nucleotide-binding pocket adopts moreflexible conformations that may facilitate nucleotide exchange), and a non-canonical state in which the G protein is rotated by about 45degrees relative to the receptor and exhibits a more rigid nucleotide-binding pocket. In the non-canonical state, NTSR1 exhibits features of both active and inactive conformations, which suggests that the structure may represent an intermediate form along the activation pathway of G proteins. This structural information, complemented by molecular dynamics simulations and functional studies, provides insights into the complex process of G-protein activation.
View details for DOI 10.1038/s41586-019-1337-6
View details for PubMedID 31243364
- Selective modulation of the cannabinoid type 1 (CB1) receptor as an emerging platform for the treatment of neuropathic pain MEDCHEMCOMM 2019; 10 (5): 647–59
- Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex CELL 2019; 176 (3): 448-+
Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex.
Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), aG protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi. Activation of CB1-Gi signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of Gi activation by CB1. Here, we present the structure of the CB1-Gi signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities. The structure illustrates how FUB stabilizes the receptor in an active state to facilitate nucleotide exchange in Gi. The results compose the structural framework to explain CB1 activation by different classes of ligands and provide insights into the G protein coupling and selectivity mechanisms adopted by the receptor.
View details for PubMedID 30639101