Structures of the human dopamine D3 receptor-Gi complexes

Xu, Peiyu; Huang, Sijie; Mao, Chunyou; Krumm, Brian E.; Zhou, Xuemei; Tan, Yangxia; Huang, Xi‐Ping; Liu, Yongfeng; Shen, Dan‐Dan; Jiang, Yi; Yu, Xuekui; Jiang, Hualiang; Melcher, Karsten; Roth, Bryan L.; Cheng, Xi; Zhang, Yan; Xu, Hao

doi:10.1016/j.molcel.2021.01.003

Cited by 61 publications

(68 citation statements)

References 59 publications

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“…The preference of fluo-cariprazine towards D 3 R over D 2 R, the classical target of antipsychotics, was also investigated at the structural and the nanoscale levels. In line with our molecular dynamics simulations using the recently published cryo-EM receptor structures 39 , 40 , fluo-cariprazine PharmacoSTORM signal was significantly reduced in D 2 R-expressing cells (Supplementary Fig. S6 ).…”

Section: Resultssupporting

confidence: 88%

PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells

et al. 2021

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Immunolabeling and autoradiography have traditionally been applied as the methods-of-choice to visualize and collect molecular information about physiological and pathological processes. Here, we introduce PharmacoSTORM super-resolution imaging that combines the complementary advantages of these approaches and enables cell-type- and compartment-specific nanoscale molecular measurements. We exploited rational chemical design for fluorophore-tagged high-affinity receptor ligands and an enzyme inhibitor; and demonstrated broad PharmacoSTORM applicability for three protein classes and for cariprazine, a clinically approved antipsychotic and antidepressant drug. Because the neurobiological substrate of cariprazine has remained elusive, we took advantage of PharmacoSTORM to provide in vivo evidence that cariprazine predominantly binds to D3 dopamine receptors on Islands of Calleja granule cell axons but avoids dopaminergic terminals. These findings show that PharmacoSTORM helps to quantify drug-target interaction sites at the nanoscale level in a cell-type- and subcellular context-dependent manner and within complex tissue preparations. Moreover, the results highlight the underappreciated neuropsychiatric significance of the Islands of Calleja in the ventral forebrain.

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Section: Resultssupporting

confidence: 88%

PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells

et al. 2021

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“…In agreement, a similar interaction was reported to play a key role in determining Gi protein coupling by members of Gi-coupled GPCRs. 20 , 41 …”

Section: Resultsmentioning

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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“…(ii) receptors that exclusively couple to Gi and have a hydrophobic residue at the position 34.51 such as D3 dopamine receptor, M2 muscarinic receptor (M2R) and μ opioid receptor (28,33,46); (iii) receptors that promiscuously couple to Gi and have a large hydrophobic residue at position 34.51 such as the neurotensin receptor 1 (NTSR1), β2AR, and the cholecystokinin A receptor (47,48). In the first class, when bound to the receptor, ICL2 is disordered, or forms a random coil structure.…”

Section: Discussionmentioning

confidence: 99%

Structural insights into the galanin receptors signaling

Zheng

Jiang

2022

Preprint

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Galanin is a biologically active neuropeptide, and functions through three distinct G protein-coupled receptors (GPCRs), namely GALR1, GALR2 and GLAR3. GALR signaling plays important roles in regulating various physiological processes such as energy metabolism, neuropathic pain, epileptic activity, and sleep homeostasis. GALR1 and GALR3 signal through the Gi/o pathway, whereas GALR2 signals mainly through the Gq/11 pathway. However, the molecular basis for galanin recognition and G protein selectivity of GALRs remains poorly understood. Here, we report the cryoelectron microscopy structures of the GALR1-Go and the GALR2-Gq complexes bound to the endogenous ligand galanin or spexin. The galanin peptide mainly adopts an alpha helical structure, which binds at the extracellular vestibule of the receptors, nearly parallel to the membrane plane without penetrating deeply into the receptor core. Structural analysis combined with functional studies reveals important structural determinants for the G protein selectivity of GALRs as well as other class A GPCRs. In addition, we show that the zinc ion is a negative allosteric regulator of GALR1 but not GALR2. Our studies provide insight into the mechanisms of G protein selectivity of GPCRs and highlight potential novel function of the neuromodulator zinc ion as a modulator of GPCR signaling in the central nervous system.

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Structures of the human dopamine D3 receptor-Gi complexes

Cited by 61 publications

References 59 publications

PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells

PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells

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

Structural insights into the galanin receptors signaling

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