The CryoEM Structure of Human GPR75: Insights into ECL2-Mediated Activation

Abstract

GPR75 is one of the most promising emerging targets for the treatment of obesity and related co-morbidities, as its loss of function directly correlates with a decreased body mass index (BMI) in humans. To date, little is known about the structure and underlying biology of GPR75, which is classified as an orphan GPCR and has low homology to other GPCRs. Here, we describe the cryoEM structure of ICL3-BRIL-fused, unliganded human GPR75, together with functional data on G-protein coupling and effects of its putative ligands. GPR75 is present in an active-like state probably induced by the structure of its extracellular loop 2 (ECL2) which folds back deeply into the orthosteric pocket. This feature is important for both receptor integrity and signaling, as shown by mutagenesis studies. This structural finding is consistent with moderate constitutive activity for Gi1, while Gq does not seem to be recruited. Furthermore, functional data indicate that the putative ligands 20-HETE and CCL5 have no measurable effect on GPR75. Significance StatementObesity is a major global health crisis which will affect a quarter of the worlds population by 2035. Many existing therapies have significant shortcomings, including emetic effects and the need for frequent injections. GPR75 is an understudied orphan GPCR which has recently emerged as one of the most promising novel obesity targets based on large-scale human genetic studies. However, the sparse knowledge we currently have about this receptor presents a major roadblock for the development of effective GPR75-based therapies. This study investigates the basic biology of GPR75 on a molecular level, including its structure and downstream signaling. These findings provide the groundwork for future efforts targeting GPR75 to fight the obesity pandemic.