Design of allosteric modulators that change GPCR G protein subtype selectivity
Year: 2024
Type: preprint
Abstract: ABSTRACT G protein-coupled receptors (GPCRs), the largest family of drug targets, can signal through 16 subtypes of Gα proteins. Biased compounds that selectively activate therapy-relevant pathways promise to be safer, more effective medications. The determinants of bias are poorly understood, however, and rationally-designed, G protein-subtype-selective compounds are lacking. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we find that small molecules binding the intracellular GPCR-transducer interface change G protein coupling by subtype-specific and predictable mechanisms, enabling rational drug design. We demonstrate that the compound SBI-553 switches NTSR1 G protein preference by acting both as a molecular bumper and a molecular glue. Structurally, SBI-553 occludes G protein binding determinants on NTSR1, promoting association with select G protein subtypes for which an alternative, shallow-binding conformation is energetically favorable. Minor modifications to the SBI-553 scaffold produce allosteric modulators with distinct G protein subtype selectivity profiles. Selectivity profiles are probe-independent, conserved across species, and translate to differences in in vivo activity. These studies demonstrate that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the receptor-transducer interface and, as this pocket is broadly conserved, present a strategy for pathway-selective drug discovery applicable to the diverse GPCR superfamily.
Authors: Madelyn N. Moore, Kelsey L. Person, Abigail Alwin, Campbell Krusemark, Noah Foster, Caroline Ray, Asuka Inoue, Michael R. Jackson, Michael J. Sheedlo, Lawrence S. Barak, Ezequiel Marron Fernandez de Velasco, Steven H. Olson, Lauren M. Slosky
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: National Institute on Drug Abuse
Awards: Leveraging Functional Selectivity in the Neurotensin Receptor 1-Mediated Treatment of Addiction, Development of SBI-553, an allosteric modulator of NTR1, for the treatment of substance use disorders, Development of SBI-553, an allosteric modulator of NTR1, for the treatment of substance use disorders, Neurotensin receptor 1 as a novel target for opioid use disorder and discovery of new small molecule probes, Center for Neural Circuits in Addiction
OpenAlex ID: W4404587234