Constitutive Arrestin Recruitment By Orphan Gpr52 Via An Atypical Binding Mode Xi Lin Xiaohu Wei Ning Pu Ling Wang Zhibin Zhang Cuixia Li Yang Yue Junlin Liu Qiwen Tan Qianqian Sun Fei Xu by Xi Lin & Xiaohu Wei & Ning Pu & Ling Wang & Zhibin Zhang & Cuixia Li & Yang Yue & Junlin Liu & Qiwen Tan & Qianqian Sun & Fei Xu instant download after payment.

1234567890();,:Dear Editor,Arrestins and G proteins are integral to G protein-coupledreceptor (GPCR) signal transduction, typically recruited followingreceptor activation by a ligand. Understanding the modes ofinteractions for arrestins provides insights into the complexity andversatility of cellular responses mediated by GPCRs. To date, only afew structures of agonist-activated GPCR–β-arrestin1 (βarr1)complexes have been resolved by cryo-electron microscopy(cryo-EM).1,2 Interestingly, most of the reported GPCR–βarr1complexes primarily exhibit core engagement conformations forβarr1, although an unstable ‘hanging’ conformation has also beenobserved for M2R–βarr1.3 In contrast, the class B GCGR–βarr1complex exhibits a tail engagement mode.2 It remains unclearwhether the core conformation is a characteristic of class Areceptors in engaging βarr1.The class A orphan receptor GPR52, highly expressed in the brain,is a potential therapeutic target for a wide range of neurologicaldisorders.4–6 Our previous work has uncovered a ‘side pocket’ inGPR52 accommodating exogenous ligand binding, underscoring itspotential for structure-guided ligand discovery and drug development.4 GPR52 exhibits a high level of basal activity without anagonist, known as constitutive activity.7 The structure of GPR52–Gscomplex in the ligand-free (apo) state and the discovery of a built-inagonist motif embedded in the extracellular loop 2 (ECL2) hasdelineated the structural basis of GPR52 self-activation in G proteinsignaling pathway.8 Recently, several groups, including ours, havereported structures of other GPCRs in complex with G proteinsin the absence of exogenous agonists.9,10 These studies havemapped the landscape of G protein coupling to constitutivelyactive GPCRs, the majority of which are orphan GPCRs. However, themechanism by which these constitutively active orphan GPCRscouple with other transducers, such as β-arrestins, remains elusive.While