Structural insight into the constitutive activity of human orphan receptor GPR12

• DOI: 10.1016/j.scib.2022.12.023
• Publication Date: 2022-12-26T16:43:51Z
• Authors: Hao Li; Jinyi Zhang; Yanan Yu; Feng Luo; Lijie Wu; Junlin Liu; Na Chen; Zhijie Liu; Tian Hua
• Keywords: Orphan receptor

G protein-coupled receptor 12 (GPR12) is an orphan that highly expressed in the thalamus of brain and plays a vital role driving thalamocortical functions short-term memory. GPR12 performs high constitutive activity couples with Gs, increasing intracellular cyclic adenosine monophosphate (cAMP) level when it expressed. However, exploitation for drug development limited since unclear how initiates self-activation signal transduction, whether can be modulated by endogenous or synthetic ligands. Here, we report cryo-electron microscopy structure GPR12-Gs complex absence agonists. Our reveals key determinants intrinsically basal GPR12, including extracellular loop 2 partially occupying orthosteric binding pocket, tight-packed TM1 TM7, unique activation-related residues TM6 TM7. Together mutagenesis data, this study will improve our understanding function enable identification ligands, guide discovery efforts target GPR12.