Structural basis of ligand recognition and self-activation of orphan GPR52

Lin, Xi; Li, Mingyue; Wang, Niandong; Wu, Yiran; Luo, Zhipu; Guo, Shimeng; Han, Gye Won; Li, Shaobai; Yang, Yongchang; Wei, Xiaohu; Xie, Xin; Chen, Yong; Zhao, Suwen; Wu, Jian; Lei, Ming; Xu, Fei

doi:10.1038/s41586-020-2019-0

Cited by 117 publications

(177 citation statements)

References 59 publications

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“…Because of the highly dynamic nature of GPCRs with multiple, functionally distinct conformational states [331,332], combined spectroscopic and computational studies allow for a detailed atomic analysis of the TM domain dynamics mediating downstream signals [333]. The most recent example is the in-depth characterized structure of GPR52 coupled to its downstream heterotrimeric Gs protein in a previously unknown self-activation state [334]. Additionally, a potential allosteric ligand-bound state was suggested as a potential drug target for Huntington's disease.…”

Section: Molecular Dynamics Simulations Of Gpcrs and Ion Channelsmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.

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Section: Molecular Dynamics Simulations Of Gpcrs and Ion Channelsmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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“…When expressed in cells, GPR52 activates Gs signaling and increases [cAMP] i in the absence of its ligand (Martin et al, 2015). Recently, Lin et al clarified the molecular structure and the mode of constitutive activity of GPR52 using crystal structure analysis (Lin et al, 2020). They found that extracellular loop 2 of GPR52 occupies the orthosteric ligand-binding pocket, which contributes to its self-activation.…”

Section: Discussionmentioning

confidence: 99%

GPR52 Accelerates Fatty Acid Biosynthesis in a Ligand-Dependent Manner in Hepatocytes and in Response to Excessive Fat Intake in Mice

et al. 2020

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Gpr52 is an orphan G-protein-coupled receptor of unknown physiological function. We found that Gpr52-deficient (Gpr52 À/À ) mice exhibit leanness associated with reduced liver weight, decreased hepatic de novo lipogenesis, and enhanced insulin sensitivity. Treatment of the hepatoma cell line HepG2 cells with c11, the synthetic GPR52 agonist, increased fatty acid biosynthesis, and GPR52 knockdown (KD) abolished the lipogenic action of c11. In addition, c11 induced the expressions of lipogenic enzymes (SCD1 and ELOVL6), whereas these inductions were attenuated by GPR52-KD. In contrast, cholesterol biosynthesis was not increased by c11, but its basal level was significantly suppressed by GPR52-KD. High-fat diet (HFD)-induced increase in hepatic expression of Pparg2 and its targets (Scd1 and Elovl6) was absent in Gpr52 À/À mice with alleviated hepatosteatosis. Our present study showed that hepatic GPR52 promotes the biosynthesis of fatty acid and cholesterol in a ligand-dependent and a constitutive manner, respectively, and Gpr52 participates in HFD-induced fatty acid synthesis in liver.

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“…A considerable number of class A GPCRs have yet unidentified endogenous ligands and are called "orphan" receptors. Whereas intense research efforts are seeking the discovery of these ligands, a recent structural study of the orphan receptor GPR52 has revealed a remarkable self-activation mechanism that might be shared by other orphan GPCRs (42). The second extracellular loop (ECL2) of the GPR52 folds into a small module that is inserted into an orthosteric (i.e.…”

Section: Structural Insights Into Gpcr Activationmentioning

confidence: 99%

Structural insights into emergent signaling modes of G protein–coupled receptors

Sutkevičiūtė

Vilardaga

2020

Journal of Biological Chemistry

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G protein–coupled receptors (GPCRs) represent the largest family of cell membrane proteins, with >800 GPCRs in humans alone, and recognize highly diverse ligands, ranging from photons to large protein molecules. Very important to human medicine, GPCRs are targeted by about 35% of prescription drugs. GPCRs are characterized by a seven-transmembrane α-helical structure, transmitting extracellular signals into cells to regulate major physiological processes via heterotrimeric G proteins and β-arrestins. Initially viewed as receptors whose signaling via G proteins is delimited to the plasma membrane, it is now recognized that GPCRs signal also at various intracellular locations, and the mechanisms and (patho)physiological relevance of such signaling modes are actively investigated. The propensity of GPCRs to adopt different signaling modes is largely encoded in the structural plasticity of the receptors themselves and of their signaling complexes. Here, we review emerging modes of GPCR signaling via endosomal membranes and the physiological implications of such signaling modes. We further summarize recent structural insights into mechanisms of GPCR activation and signaling. We particularly emphasize the structural mechanisms governing the continued GPCR signaling from endosomes and the structural aspects of the GPCR resensitization mechanism, and discuss the recently uncovered and important roles of lipids in these processes.

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Structural basis of ligand recognition and self-activation of orphan GPR52

Cited by 117 publications

References 59 publications

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

GPR52 Accelerates Fatty Acid Biosynthesis in a Ligand-Dependent Manner in Hepatocytes and in Response to Excessive Fat Intake in Mice

Structural insights into emergent signaling modes of G protein–coupled receptors

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