Structural insights into the human D1 and D2 dopamine receptor signaling complexes

Zhuang, Yahui; Xu, Peiyu; Mao, Chunyou; Wang, Lei; Krumm, Brian E.; Zhou, Xuemei; Huang, Sijie; Liu, Heng; Cheng, Xi; Huang, Xi‐Ping; Shen, Dan‐Dan; Xu, Tianyuan; Liu, Yongfeng; Wang, Yue; Guo, Jia; Jiang, Yi; Jiang, Hualiang; Melcher, Karsten; Roth, Bryan L.; Zhang, Yan; Zhang, Cheng; Xu, Hao

doi:10.1016/j.cell.2021.01.027

Cited by 185 publications

(170 citation statements)

References 59 publications

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“…The Gs protein heterotrimer was the first transducer to be solved in complex with an activated GPCR (39), and multiple complexes with Gs have now been determined for class A and class B GPCRs where Gs is the primary transducer (7,(10)(11)(12)(40)(41)(42)(43)(44). These structures have revealed both common and diverse features that govern Gs binding.…”

Section: Gs Proteinsmentioning

confidence: 99%

Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins: insight into mechanisms of G protein selectivity

Mobbs

Belousoff

Harikumar³

et al. 2021

Preprint

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G protein-coupled receptors (GPCRs) are critical regulators of cellular function acting via heterotrimeric G proteins as their primary transducers with individual GPCRs capable of pleiotropic coupling to multiple G proteins. Structural features governing G protein selectivity and promiscuity are currently unclear. Here we used cryo-electron microscopy to determine structures of the CCK1R bound to the CCK peptide agonist, CCK-8 and two distinct transducer proteins, its primary transducer Gq, and the more weakly coupled Gs. As seen with other Gq/11-GPCR complexes, the Gq-α5 helix bound to a relatively narrow pocket in the CCK1R core. Surprisingly, the backbone of the CCK1R and volume of the G protein binding pocket was essentially equivalent when Gs was bound, with the Gs α5 helix displaying a conformation that arises from "unwinding" of the far C-terminal residues, compared to canonically Gs coupled receptors. Thus, integrated changes in the conformations of both the receptor and G protein play critical roles in the promiscuous coupling of individual GPCRs.

show abstract

Section: Gs Proteinsmentioning

confidence: 99%

Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins: insight into mechanisms of G protein selectivity

Mobbs

Belousoff

Harikumar³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Three recent articles published in Cell 1 , 2 and Cell Research 3 have reported multiple cryo-electron microscopy (cryo-EM) structures of the D1 dopamine receptor (DRD1) bound to either dopamine, various DRD1 agonists, or a positive allosteric modulator (PAM), while in complex with the active heterotrimeric G s protein. These studies describe for the first time active-state structures of the DRD1, an exciting advancement in the field that will allow for a better understanding of selective agonist binding, DRD1 activation, G protein selectivity, and the provision of multiple templates to facilitate future drug design and discovery for this important therapeutic target.…”

mentioning

confidence: 99%

“…The binding pockets are indicated by the ellipses in the same colors as the central panel. Those from Xiao, et al 1 are colored in cyan, those from Zhuang, et al 2 , 3 are colored in orange. In particular, three pairs of structures bound with dopamine, SKF83959, or LY3154207 from both groups are superimposed to demonstrate their divergences …”

mentioning

confidence: 99%

“…Zhuang, et al 2 simultaneously reported three cryo-EM structures of a DRD1-G s complex bound to three catechol-containing agonists including the benzazepines SKF81297 (a full agonist) and SKF83959, as well as the pan dopamine receptor agonist apomorphine, which is used to treat Parkinson’s disease 2 (Fig. 1 ).…”

mentioning

confidence: 99%

“…1 ). 1 , 2 Interestingly, from comparing the poses of the structurally related agonists SKF81297 (non-biased) and SKF83959 (G-protein-biased), it was suggested that steric packing between the methyl group in the azepine ring of SFK83959 and residues in TM7 may explain its signaling bias; 2 however, a complete understanding of this mechanism will likely require the structural elucidation of a DRD1-β-arrestin complex.…”

mentioning

confidence: 99%

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Novel Cryo-EM structures of the D1 dopamine receptor unlock its therapeutic potential

Sibley

Luderman

Free

et al. 2021

Sig Transduct Target Ther

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Bionanoscale Recognition Underlies Cell Fate and Therapy

Sun

Deng

et al. 2021

Adv Healthcare Materials

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Understanding the bionanoscale recognition of nanostructured architectures is critical to the design and application of nanomaterials, but the related information is not well understood. In this study, it is found that bionanoscale recognition underlies cell fate and therapy. For example, 1T phase (octahedral coordination) monolayer MoS 2 exhibits a markedly stronger affinity for fibronectin than the 2H structure (triangular prism coordination) and promotes cell spreading and differentiation. The van der Waals energy and increased turn components contribute to the high adhesion of fibronectin onto the 1T-MoS 2 structure. 1T-MoS 2 exhibits a significantly stronger affinity (K D , 6.59 × 10 −7 m) for liposomes than 2H-MoS 2 (1.21 × 10 −6 m) due to strong hydrophobic interactions. The existence of octahedrally coordinated atomic structures that improve cell viability by enhancing the neurite length is first proven by random forest and structural equation models. Consequently, octahedral coordination disaggregates 𝜶-synuclein (e.g., by decreasing 𝜷-sheets and increasing coil structures) and protects cells and hosts against Parkinson's disease. As a proof-of-principle demonstration, these findings indicate that bionanoscale recognition underlies the design of biomaterials and cell therapeutics.

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Structural insights into the human D1 and D2 dopamine receptor signaling complexes

Cited by 185 publications

References 59 publications

Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins: insight into mechanisms of G protein selectivity

Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins: insight into mechanisms of G protein selectivity

Novel Cryo-EM structures of the D1 dopamine receptor unlock its therapeutic potential

Bionanoscale Recognition Underlies Cell Fate and Therapy

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