Clovertex Target of the Month (09/23): GPR61

September's Clovertex Target of the Month is GPR61 following Pfizer's recent publication concerning this orphan GPCR. GPR61, expressed in the brain, is associated with phenotypes affecting appetite. This positions it as a promising candidate for addressing disorders like obesity and cachexia. A challenge in harnessing GPR61's potential has been the absence of comprehensive structural information, known biological ligands, and robust tool compounds.

A significant highlight of the study is the discovery of a potent, selective small-molecule inverse agonist for GPR61. Cryo-EM structures of its active-like complex with the hetero-trimeric G protein and its inactive state illuminate how this tool molecule achieves inverse agonism via an allosteric mechanism. These results not only shed light on the mechanisms of an orphan GPCR but also furnish a structural blueprint, accompanied by a tool compound, that could serve as an excellent starting point for drug discovery, bolstering continued research into GPR61's function and regulation.

A very noteworthy aspect of the article lies in the methodology employed to elucidate the inactive-state structure of GPR61 involving a BRIL-fusion approach. Initially, 25 GPR61-BRIL fusion constructs were designed and screened by cryo-EM, which only yielded a resolution of only approximately 6Å. The subsequent availability of AlphaFold 2 then suggested that AlphaFold predictions could be useful for construct optimization. Indeed, using an AlphaFold-first strategy for construct optimization suggested four new constructs of which one proved very successful for cryo-EM at high resolution. With the availability of cryo-EM structures for both active and inactive states of GPR61, the paper features valuable comparisons among AlphaFold 2 and AlphaFold MultiState predictions as well as the actual cryo-EM structures, of course. The protein model rendering depicts the AlphaFold 2 prediction of the human GPR61.

About Clovertex

Clovertex is an industry leader specializing in meeting the scientific IT needs of pharmaceutical companies, with a robust focus on cloud-based or on-premises cryo-EM processing. As an Advanced Tier Services Partner with Amazon Web Services (AWS), Clovertex leverages its comprehensive expertise to architect, build, automate, and manage software applications designed to meet specific research needs. Our all-encompassing solutions are meticulously tailored to streamline the complex processes associated with pharmaceutical research, underscoring our commitment to innovation, efficiency, and customer satisfaction. By integrating state-of-the-art technology with deep scientific understanding, Clovertex paves the way in optimizing the intersection of information technology and pharmaceutical development.

Useful links

1. An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism.

2. Clovertex website