An aromatic amino acid within intracellular loop 2 of the prostaglandin EP2 receptor is a prerequisite for selective association and activation of Gαs

Yano, Akiko; Takahashi, Yuko; Moriguchi, Hiromi; Inazumi, Tomoaki; Koga, Tomoaki; Otaka, Akira; Sugimoto, Yukihiko

doi:10.1016/j.bbalip.2017.03.006

Cited by 5 publications

(10 citation statements)

References 29 publications

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“…We next sought to determine the importance of interactions between Gs and ICL2 in GDP release. It has previously been shown that mutation of F139A impaired cyclic AMP (cAMP) accumulation in cultured cells (Yano et al, 2017). As shown in Figure 4D, the F139A mutant was unable to trigger GDP release.…”

Section: Time-resolved Structural Changes In Gas During Gpcr-gs Couplingmentioning

confidence: 79%

“…The aN/b1 hinge and b1 strand at the amino terminus of the Ras-like domain links ICL2 with the P loop that binds the diphosphate of GDP (Figures 1C and 1D). Much has been learned about the detailed structural features and conformational dynamics of these two allosteric pathways using a variety of biophysical, biochemical, and computational approaches on different GPCR-G protein pairs (Alexander et al, 2014;Dror et al, 2015;Kaya et al, 2014;Moro et al, 1993;Nanoff et al, 2006;Oldham et al, 2006Oldham et al, , 2007Scheerer et al, 2009;Van Eps et al, 2011;Yano et al, 2017;Zhou et al, 1999). Nevertheless, understanding the temporal sequence of these substantial conformational changes during GPCR-mediated G protein activation are likely to provide additional insights into GPCR-G protein coupling selectivity (Preininger et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Assembly of a GPCR-G Protein Complex

Duc

Rasmussen

et al. 2019

Cell

179

187

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Section: Time-resolved Structural Changes In Gas During Gpcr-gs Couplingmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Assembly of a GPCR-G Protein Complex

Duc

Rasmussen

et al. 2019

Cell

179

187

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“…14a). A positionally equivalent aromatic (Phe or Tyr) is seen in most active, G protein-complexed, class B GPCR structures solved to date 12 , as well as the class A Gscoupled EP2 and β2-adrenergic receptors 28,29 , although select class B GPCRs have a lipophilic Leu, and the GIPR has a distinct Fig. 4 Interactions between SecR and secretin during MD simulations.…”

Section: Resultsmentioning

confidence: 99%

“…14a ). A positionally equivalent aromatic (Phe or Tyr) is seen in most active, G protein-complexed, class B GPCR structures solved to date 12 , as well as the class A Gs-coupled EP2 and β2-adrenergic receptors 28 , 29 , although select class B GPCRs have a lipophilic Leu, and the GIPR has a distinct sequence 12 . It is hypothesized that interactions between ICL2 and the G protein may contribute to G protein activation, contributing to conformational changes in the G protein linked to GDP release 28 .…”

Section: Resultsmentioning

confidence: 99%

Structure and dynamics of the active Gs-coupled human secretin receptor

et al. 2020

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The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2.3 Å structure, and interrogate dynamics, of secretin bound to the SecR:Gs complex. SecR exhibited a unique organization of its extracellular domain (ECD) relative to its 7-transmembrane (TM) core, forming more extended interactions than other family members. Numerous polar interactions formed between secretin and the receptor extracellular loops (ECLs) and TM helices. Cysteine-cross-linking, cryo-electron microscopy multivariate analysis and molecular dynamics simulations revealed that interactions between peptide and receptor were dynamic, and suggested a model for initial peptide engagement where early interactions between the far N-terminus of the peptide and SecR ECL2 likely occur following initial binding of the peptide C-terminus to the ECD.

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“…No robust density was observed beyond amino acid 402 of the CLR C terminus or 142 of the RAMP1 C terminus. In the CGRP-bound structure, only density for the C terminus (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37) of the peptide was resolved in the consensus map (Fig. 1D).…”

mentioning

confidence: 99%

Structure and dynamics of the CGRP receptor in apo and peptide-bound forms

Josephs

Belousoff

Liang

et al. 2021

Science

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G protein-coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only limited understanding of the behavior of GPCRs in the apo state and the conformational changes upon agonist binding that lead to G protein recruitment and activation. We expressed and purified unmodified apo and peptide-bound calcitonin gene-related peptide (CGRP) receptors to determine their cryo-EM structures and complemented these with analysis of protein conformational dynamics using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and 3D variance analysis of the cryo-EM data. Together with our previously published structure of the active, Gs-bound, CGRP receptor complex, our work provides important insight into mechanisms of class B1 GPCR activation.

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An aromatic amino acid within intracellular loop 2 of the prostaglandin EP2 receptor is a prerequisite for selective association and activation of Gαs

Cited by 5 publications

References 29 publications

Assembly of a GPCR-G Protein Complex

Assembly of a GPCR-G Protein Complex

Structure and dynamics of the active Gs-coupled human secretin receptor

Structure and dynamics of the CGRP receptor in apo and peptide-bound forms

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