Functional elements of the gastric inhibitory polypeptide receptor: Comparison between secretin- and rhodopsin-like G protein-coupled receptors

Cordomí, Arnau; Ismail, Sadek; Matsoukas, Minos‐Timotheos; Escrieut, Chantal; Gherardi, Marie-Julie; Pardo, Leonardo; Fourmy, Daniel

doi:10.1016/j.bcp.2015.05.015

Cited by 17 publications

(23 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Monomeric mGlu 2 receptors couple to G proteins upon activation by a PAM alone (El Moustaine et al, 2012) while PAM binding in only one allosteric site in the mGlu homodimer can achieve maximal potentiation (Goudet et al, 2005). Therefore we hypothesize similarities in receptor (in)activation for classes A and C, as previously suggested for family B (Cordomí et al, 2015;Spyridaki et al, 2014). Thus, (in)activation of mGlu 2 receptors involves rearrangement of an analogous ''transmission switch'' in TM3, TM5, and TM6, involving positions 3.40a, 5.50a, and 6.44a, as described for class A (inward movement of TM5 at the highly conserved P 5.50a , steric competition between a bulky hydrophobic side chain at position 3.40a, counterclockwise rotation of TM3 when viewed from the extracellular side, reposition of F 6.44a , and outward movement of TM6 for receptor activation) (Sansuk et al, 2011;Venkatakrishnan et al, 2013).…”

Section: Mechanisms Of Receptor (In)activation By Pams and Namssupporting

confidence: 71%

Molecular Switches of Allosteric Modulation of the Metabotropic Glutamate 2 Receptor

et al. 2017

Self Cite

View full text Add to dashboard Cite

Metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) crucial for CNS function and important drug discovery targets. Glutamate triggers receptor activation from an extracellular domain binding site while allosteric modulators bind in the seven-transmembrane domain. Little is known about how allosteric modulators produce their functional effects at the molecular level. Here we address this topic with combined experimental and computational approaches and reveal that mGlu receptor allosteric modulators interact with the homologous "trigger switch" and "transmission switch" amino acids as seen in class A GPCRs, in short, the characteristic hallmarks of class A agonist activation translate to the mGlu allosteric modulator. The proposed "trigger switch" for the mGlu involves the side chains of F643, N735, and W773, whereas the "transmission switch" involves the Y647, L738, and T769 amino acids. The work has wide impact on understanding mGlu GPCR function and for future allosteric modulator drugs.

show abstract

Section: Mechanisms Of Receptor (In)activation By Pams and Namssupporting

confidence: 71%

Molecular Switches of Allosteric Modulation of the Metabotropic Glutamate 2 Receptor

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…1D, E). Mutagenesis studies on different class B1 receptors confirmed the involvement of both positions in receptor activation (39,(47)(48)(49). In ADGRs, a tryptophan at position 6.48/7.53b is 100% conserved and alanine substitution resulted in a complete loss of both activity and cell surface expression.…”

Section: Motifs Important For Adgr Function In Tm6 and Tm7 Resemble Bmentioning

confidence: 83%

Getting from A to B—exploring the activation motifs of the class B adhesion G protein‐coupled receptor subfamily G member 4/GPR112

et al. 2016

View full text Add to dashboard Cite

The adhesion G protein‐coupled receptors [ADGRs/class B2 G protein‐coupled receptors (GPCRs)] constitute an ancient family of GPCRs that have recently been demonstrated to play important roles in cellular and developmental processes. Here, we describe a first insight into the structure‐function relationship of ADGRs using the family member ADGR subfamily G member 4 (ADGRG4)/GPR112 as a model receptor. In a bio‐informatics approach, we compared conserved, functional elements of the well‐characterized class A and class B1 secretin‐like GPCRs with the ADGRs. We identified several potential equivalent motifs and subjected those to mutational analysis. The importance of the mutated residues was evaluated by examining their effect on the high constitutive activity of the N‐terminally truncated ADGRG4/GPR112 in a 1‐receptor‐1‐G protein Saccharomyces cerevisiae screening system and was further confirmed in a transfected mammalian human embryonic kidney 293 cell line. We evaluated the results in light of the crystal structures of the class A adenosine A2A receptor and the class B1 corticotropin‐releasing factor receptor 1. ADGRG4 proved to have functionally important motifs resembling class A, class B, and combined elements, but also a unique highly conserved ADGR motif (H3.33). Given the high conservation of these motifs and residues across the adhesion GPCR family, it can be assumed that these are general elements of ADGR function.—Peeters, M. C., Mos, I., Lenselink, E. B., Lucchesi, M., IJzerman, A. P., Schwartz, T. W. Getting from A to B—exploring the activation motifs of the class B adhesion G protein‐coupled receptor subfamily G member 4/GPR112. FASEB J. 30, 1836–1848 (2016). http://www.fasebj.org

show abstract

“…While we believe it is possible to identify considerable conservation of mechanisms involving the hydrophobic networks both between and within GPCR families, the data also show how elements of this network are uniquely adapted in individual receptors. Thus residue 6.48 is a key part of the hydrophobic network in class A GPCRs and the CRFR1 [46] ; in the GIPR and GLP-1 receptors it takes part in a hydrophilic network [15] , [58] , [59] , [60] , but it only appears significant on alanine mutation for CLR/RAMP2 and RAMP3, not RAMP1. Furthermore, E354A 6.48 increases GIP potency at the GIPR showing the main effect of the residue is to stabilize the inactive state of the receptor but for CLR/RAMP2 and RAMP3, mutation of F349 6.48/6.53b impairs activation [15] , [46] .…”

Section: Discussionmentioning

confidence: 99%

Receptor activity-modifying protein dependent and independent activation mechanisms in the coupling of calcitonin gene-related peptide and adrenomedullin receptors to Gs

Woolley

Reynolds

Simms

et al. 2017

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

Functional elements of the gastric inhibitory polypeptide receptor: Comparison between secretin- and rhodopsin-like G protein-coupled receptors

Cited by 17 publications

References 56 publications

Molecular Switches of Allosteric Modulation of the Metabotropic Glutamate 2 Receptor

Molecular Switches of Allosteric Modulation of the Metabotropic Glutamate 2 Receptor

Getting from A to B—exploring the activation motifs of the class B adhesion G protein‐coupled receptor subfamily G member 4/GPR112

Receptor activity-modifying protein dependent and independent activation mechanisms in the coupling of calcitonin gene-related peptide and adrenomedullin receptors to Gs

Contact Info

Product

Resources

About