Cryo-EM complex structure of active GPR75 with a nanobody

Abstract

Although there has been enormous progress in the last half-century in the drug discovery targeting obesity and associated co-morbidities, the clinical treatment of obesity remains tremendously challenging. GPR75 is an orphan receptor and is suggested to be a potential novel target for the control of obesity and related metabolic disorders. Inhibition of the GPR75 signaling pathway by small molecules, antibodies, or genetic manipulations may provide a therapeutic strategy for obesity. Here, we report the active-like Cryo-EM structure of human GPR75 with an intracellular nanobody, which reveals the receptor activation mechanism. The extensive interaction network required to achieve the active structure helps explain the allosteric coupling between the orthosteric pocket and the G-protein coupling domain. The well-defined orthosteric ligand binding pocket of human GPR75 provides a structural basis for anti-obesity drug discovery.

Nanobodies as Diagnostic and Therapeutic Tools for Cardiovascular Diseases (CVDs)

“…In an attempt to solve the lack of combat methods, scientists tried to analyze receptor GPR75 (G Protein Receptor), a new target for the treatment of obesity, using an intracellular nanobody. Using cryo-electron microscopy (Cryo-EM), they studied the GPR75-nanobody complex (NbH3) and were able to obtain information about the activation of the receptor, which is crucial information in the race for a new therapeutic agent anti-obesity [ 64 ].…”

“…The progression of atherosclerosis in mice and rabbits was evaluated using radiolabeled nanobodies with 64 Cu for the screening of specific biomarkers such as (VCAM)-1, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and MMR. The nanobodies functionalized with 1,4,7-triazacyclononane-1,4,7-triacetic acid showed good results for in vivo screening in ApoE −/− mice, with 64 Cu deposition observed at the aortic root for the MMR nanobody in particular. In addition, the MMR nanobody was labeled with gallium-68 ( 68 Ga) to phenotype rabbit atherosclerotic aortas using PET/MRI imaging compared with clinically available radiotracers 18 F-FDG and 18 F-NaF.…”