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Cited by 392Receptor Mechanisms and SignalingProtein Kinase Regulation and GTPase SignalingNeuroscience and Neuropharmacology Research

The Highly Conserved DRY Motif of Class A G Protein-Coupled Receptors: Beyond the Ground State

Rovati, G. Enrico, Capra, Valérie, Neubig, Richard R.·2007·Molecular Pharmacology
DOI 10.1124/mol.106.029470
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Abstract

Despite extensive study of heptahelical G protein-coupled receptors (GPCRs), the precise mechanism of G protein activation is unknown. The role of one highly conserved stretch of residues, the amino acids glutamic acid/aspartic acid-arginine-tyrosine (i.e., the E/DRY motif), has received considerable attention with respect to regulating GPCR conformational states. In the consensus view, glutamic acid/aspartic acid maintains the receptor in its ground state, because mutations frequently induce constitutive activity (CA). This hypothesis has been confirmed by the rhodopsin ground-state crystal structure and by computational modeling approaches. However, some class A GPCRs are resistant to CA, suggesting alternative roles for the glutamic acid/aspartic acid residue and the E/DRY motif. Here, we propose two different subgroups of receptors within class A GPCRs that make different use of the E/DRY motif, independent of the G protein type (G(s), G(i), or G(q)) to which the receptor couples. In phenotype 1 receptors, nonconservative mutations of the glutamic acid/aspartic acid-arginine residues, besides inducing CA, increase affinity for agonist binding, retain G protein coupling, and retain an agonist-induced response. In contrast, in second phenotype receptors, the E/DRY motif is more directly involved in governing receptor conformation and G protein coupling/recognition. Hence, mutations of the glutamic acid/aspartic acid residues do not induce CA. Conversely, nonconservative mutations of the arginine of the E/DRY motif always impair agonist-induced receptor responses and, generally, reduce agonist binding affinity. Thus, it is essential to look beyond the rhodopsin ground-state model of conformational activation to clarify the role of this highly conserved triplet in GPCR activation and function.

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  • The Leu148Ser substitution in the KiSS-1 receptor is located near the DRW(Y) motif, which has an important role in regulating activation and inactivation of many G-protein-coupled receptors.

    “This substitution is located near the DRW(Y) motif, a motif that has an important role in regulating the activation and inactivation of many G-protein-coupled receptors.”

    From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [49]

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Authors
Rovati, G. E., Capra, V., & Neubig, R. R.
Affiliations
University of Milan (IT)
ORCID
Venue
Molecular Pharmacology
Publisher
Elsevier BV
Published
2007-04
Volume
71
Issue
4
Pages
959-964
ISSN
0026-895X (ISSN-L)
DOI
10.1124/mol.106.029470
OpenAlex
W2139945041
Cited by
392
References
71
Citations by year
2026: 14 · 2025: 21 · 2024: 13 · 2023: 21 · 2022: 15 · 2021: 20 · 2020: 14 · 2019: 22 · 2018: 22 · 2017: 21 · 2016: 22 · 2015: 23 · 2014: 20 · 2013: 19 · 2012: 25
FWCI
1.41
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Molecular Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
class A G protein-coupled receptors, constitutive activity, receptor conformational states, agonist affinity, G protein coupling
MeSH terms
Mutation, Protein Conformation, Conserved Sequence, GTP-Binding Proteins, Amino Acid Motifs, Receptors, G-Protein-Coupled

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