Structures of the glucocorticoid-bound adhesion receptor GPR97–Go complex

Ping, Yu; Mao, Chunyou; Peng, Xiao; Zhao, Ru-Jia; Jiang, Yi; Yang, Zhao; An, Wen-Tao; Shen, Dan‐Dan; Yang, Fan; Zhang, Huibing; Qu, Changxiu; Shen, Qingya; Tian, Caiping; Li, Zijian; Li, Shaolong; Wang, Guangyu; Tao, Xiao-Na; Wen, Xin; Zhong, Ya-Ni; Yang, Jing; Yi, Fan; Yu, Xiao; Xu, Hao; Zhang, Yan; Sun, Junying

doi:10.1038/s41586-020-03083-w

Cited by 97 publications

(60 citation statements)

References 55 publications

(44 reference statements)

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“…To measure the cell surface expression level of receptors, enzyme-linked immunosorbent assay (ELISA) was performed in our study as described in the previous study. 57 Briefly, CHO-K1 cells were transiently transfected with wild-type and mutants of S1PR1 and S1PR5 (pcDNA3.1+ as a vehicle) using jetPRIME transfection reagent. After 24 h incubation, the transfected cells were plated in poly-lysine-coated 96-well cell culture plates and incubated overnight.…”

Section: Methodsmentioning

confidence: 99%

Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition

Yuan

Jia

et al. 2021

Cell Res

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Sphingosine-1-phosphate (S1P) is an important bioactive lipid molecule in cell membrane metabolism and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, physiological homeostasis, and pathogenic processes in various organs. S1PRs are lipid-sensing receptors and are therapeutic targets for drug development, including potential treatment of COVID-19. Herein, we present five cryo-electron microscopy structures of S1PRs bound to diverse drug agonists and the heterotrimeric Gi protein. Our structural and functional assays demonstrate the different binding modes of chemically distinct agonists of S1PRs, reveal the mechanical switch that activates these receptors, and provide a framework for understanding ligand selectivity and G protein coupling.

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Section: Methodsmentioning

confidence: 99%

Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition

Yuan

Jia

et al. 2021

Cell Res

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“…Similarly, a recent work published by Sun JP and coworkers demonstrated that palmitoylation on C351 at the cytosolic tail of the G o protein was essential for efficient engagement with adhesion G-protein-coupled receptor G3 (ADGRG3) but was not observed in other GPCR complex structures. They observed that the palmitoylation on G o inserted deeply into the 7TM core and interacted with H362 3.53 and L363 3.54 of GPR97, the intracellular loop 1 (ICL1) of the receptor adopted a one-turn helical structure that formed direct contacts with Gβ 58 . We propose here a similar allosteric regulating mechanism that S-nitrosylation of GNIA2 promotes the ability of CXCR5 rather than other GPCRs to engage its active Gi protein-coupled state.…”

Section: Discussionmentioning

confidence: 99%

S-nitrosylation-mediated coupling of G-protein alpha-2 with CXCR5 induces Hippo/YAP-dependent diabetes-accelerated atherosclerosis

et al. 2021

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Atherosclerosis-associated cardiovascular disease is one of the main causes of death and disability among patients with diabetes mellitus. However, little is known about the impact of S-nitrosylation in diabetes-accelerated atherosclerosis. Here, we show increased levels of S-nitrosylation of guanine nucleotide-binding protein G(i) subunit alpha-2 (SNO-GNAI2) at Cysteine 66 in coronary artery samples from diabetic patients with atherosclerosis, consistently with results from mice. Mechanistically, SNO-GNAI2 acted by coupling with CXCR5 to dephosphorylate the Hippo pathway kinase LATS1, thereby leading to nuclear translocation of YAP and promoting an inflammatory response in endothelial cells. Furthermore, Cys-mutant GNAI2 refractory to S-nitrosylation abrogated GNAI2-CXCR5 coupling, alleviated atherosclerosis in diabetic mice, restored Hippo activity, and reduced endothelial inflammation. In addition, we showed that melatonin treatment restored endothelial function and protected against diabetes-accelerated atherosclerosis by preventing GNAI2 S-nitrosylation. In conclusion, SNO-GNAI2 drives diabetes-accelerated atherosclerosis by coupling with CXCR5 and activating YAP-dependent endothelial inflammation, and reducing SNO-GNAI2 is an efficient strategy for alleviating diabetes-accelerated atherosclerosis.

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“…More of the latter are thus needed, which has been recently boosted by remarkable advances in the cryo-EM technique for solving the active GPCR-G protein complex structures. More experimental structures are also needed for the class B and C GPCRs, especially the class B2 GPCRs for which the first structure has been obtained only very recently (Ping et al, 2021). Only a handful of structures are currently available for the GPCRs bound by allosteric modulators.…”

Section: Discussionmentioning

confidence: 99%

Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

Hung

Haldane

Levy

et al. 2021

Preprint

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G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs. Functional mechanisms of GPCRs remain poorly understood. Here, we have constructed sequence coevolutionary models of the A, B and C classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts have been successfully detected in the sequence-based covariational models. "Exception" residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Our combined coevolutionary and structural analysis revealed unique features of the different classes of GPCRs. First, we provided evidence from coevolutionary couplings that dimerization is required for activation of class C GPCRs, but not for activation of class A and B GPCRs. Second, we identified distinct residue contacts involving different sets of functional motifs for activation of the class A and B GPCRs. Finally, we uncovered critical residue contacts tuned by allosteric modulation in the three classes of GPCRs. These findings provide a promising framework for designing selective therapeutics of GPCRs.

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Structures of the glucocorticoid-bound adhesion receptor GPR97–Go complex

Cited by 97 publications

References 55 publications

Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition

Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition

S-nitrosylation-mediated coupling of G-protein alpha-2 with CXCR5 induces Hippo/YAP-dependent diabetes-accelerated atherosclerosis

Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

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