Cryo-EM Structure of the Prostaglandin E Receptor EP4 Coupled to G Protein

Nojima, Shingo; Fujita, Yöko; Kimura, Kanako; Nomura, Norimichi; Suno, Ryoji; Morimoto, Kazushi; Yamamoto, Masaki; Noda, Takeshi; Iwata, So; Shigematsu, Hideki; Kobayashi, Takuya

doi:10.1016/j.str.2020.11.007

Cited by 35 publications

(43 citation statements)

References 52 publications

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“…Gs proteins. 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 PLOS BIOLOGY structures have revealed both common and diverse features that govern Gs binding.…”

Section: Comparison Of Cck1r G Protein Engagement With Coupling Of Canonical G Protein Partners In Other Gpcrsmentioning

confidence: 99%

“…In these GPCR–Gs complex structures, TM6 is splayed further away from the core than is seen for Gi/o or Gq/11 complexes where these are the primary transducers. However, in more recent class A GPCR–Gs complexes, greater divergence in the conformation of the intracellular TM helix ends has been observed [ 11 , 12 ]. Moreover, in the EP4 receptor, the carboxyl-terminal Gαs “hook” unwinds to enable novel engagement with the receptor [ 11 ] that could also enable binding of Gs to receptors that have narrower intracellular cavities when activated.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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 (cryo-EM) to determine structures of the cholecystokinin (CCK) type 1 receptor (CCK1R) bound to the CCK peptide agonist, CCK-8 and 2 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 (αH5) bound to a relatively narrow pocket in the CCK1R core. Surprisingly, the backbone of the CCK1R and volume of the G protein binding pocket were essentially equivalent when Gs was bound, with the Gs αH5 displaying a conformation that arises from “unwinding” of the far carboxyl-terminal residues, compared to canonically Gs coupled receptors. Thus, integrated changes in the conformations of both the receptor and G protein are likely to play critical roles in the promiscuous coupling of individual GPCRs.

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Section: Comparison Of Cck1r G Protein Engagement With Coupling Of Canonical G Protein Partners In Other Gpcrsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In these GPCR-Gs complex structures, TM6 is splayed further away from the core than is seen for Gi/o or Gq/11 complexes where these are the primary transducers. However, in more recent class A GPCR-Gs complexes greater divergence in the conformation of the intracellular TM helix ends has been observed (11,12). Moreover, in the EP4 receptor, the C-terminal Gas "hook" unwinds to enable novel engagement with the receptor (11) that could also enable binding of Gs to receptors that have narrower intracellular cavities when activated.…”

Section: Main Textmentioning

confidence: 99%

“…However, in more recent class A GPCR-Gs complexes greater divergence in the conformation of the intracellular TM helix ends has been observed (11,12). Moreover, in the EP4 receptor, the C-terminal Gas "hook" unwinds to enable novel engagement with the receptor (11) that could also enable binding of Gs to receptors that have narrower intracellular cavities when activated. The aH5 of Gi/o or Gq/11 proteins is less bulky and these proteins can be readily accommodated with smaller outward movement of TM6.…”

Section: Main Textmentioning

confidence: 99%

“…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%

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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.

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