Identification of Key Structural Motifs Involved in 7 Transmembrane Signaling of Adhesion GPCRs

Marta Arimont Segura, Melanie van der Woude, Rob Leurs, H.F. Vischer, Chris de Graaf, Saskia Nijmeijer

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The adhesion class B2 family of G protein-coupled receptors (GPCRs) plays a key role in important physiological processes and their dysfunction is linked to brain malformations and tumorigenesis. Although information regarding their signaling properties is starting to emerge, the structural motifs and interaction networks that determine 7 transmembrane (TM) signaling of class B2 GPCRs remain to be elucidated. Comparative sequence–structure analyses of class B2 GPCRs and the recently solved active class B1 structures show that class B2 GPCRs include different elements of the conserved residue motifs that determine class B1 activation. Combined site-directed mutagenesis and molecular dynamics studies were performed to give detailed insights into the role of 7TM interaction networks in signaling of two representative class B2 receptors, ADGRG1 (GPR56) and ADGRL4 (ELTD1). The systematic investigation of class B1/B2 sequence motifs provides consistent structure–function relationships that can be translated to the whole class B2 GPCR family and suggests that class B1 and B2 GPCRs share conserved intramolecular 7TM interactions. This improved understanding in adhesion GPCR structure and constitutive signaling can accelerate drug design campaigns for this chemically unexplored receptor class.
Original languageEnglish
Pages (from-to)101-113
Number of pages13
JournalACS Pharmacology & Translational Science
Volume2
Issue number2
DOIs
Publication statusPublished - 21 Jan 2019

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G-Protein-Coupled Receptors
Physiological Phenomena
Drug Design
Molecular Dynamics Simulation
Site-Directed Mutagenesis
Carcinogenesis
Brain

Cite this

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title = "Identification of Key Structural Motifs Involved in 7 Transmembrane Signaling of Adhesion GPCRs",
abstract = "The adhesion class B2 family of G protein-coupled receptors (GPCRs) plays a key role in important physiological processes and their dysfunction is linked to brain malformations and tumorigenesis. Although information regarding their signaling properties is starting to emerge, the structural motifs and interaction networks that determine 7 transmembrane (TM) signaling of class B2 GPCRs remain to be elucidated. Comparative sequence–structure analyses of class B2 GPCRs and the recently solved active class B1 structures show that class B2 GPCRs include different elements of the conserved residue motifs that determine class B1 activation. Combined site-directed mutagenesis and molecular dynamics studies were performed to give detailed insights into the role of 7TM interaction networks in signaling of two representative class B2 receptors, ADGRG1 (GPR56) and ADGRL4 (ELTD1). The systematic investigation of class B1/B2 sequence motifs provides consistent structure–function relationships that can be translated to the whole class B2 GPCR family and suggests that class B1 and B2 GPCRs share conserved intramolecular 7TM interactions. This improved understanding in adhesion GPCR structure and constitutive signaling can accelerate drug design campaigns for this chemically unexplored receptor class.",
author = "{Arimont Segura}, Marta and {van der Woude}, Melanie and Rob Leurs and H.F. Vischer and {de Graaf}, Chris and Saskia Nijmeijer",
year = "2019",
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doi = "10.1021/acsptsci.8b00051",
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Identification of Key Structural Motifs Involved in 7 Transmembrane Signaling of Adhesion GPCRs. / Arimont Segura, Marta; van der Woude, Melanie; Leurs, Rob; Vischer, H.F.; de Graaf, Chris; Nijmeijer, Saskia.

In: ACS Pharmacology & Translational Science, Vol. 2, No. 2, 21.01.2019, p. 101-113.

Research output: Contribution to JournalArticleAcademicpeer-review

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AB - The adhesion class B2 family of G protein-coupled receptors (GPCRs) plays a key role in important physiological processes and their dysfunction is linked to brain malformations and tumorigenesis. Although information regarding their signaling properties is starting to emerge, the structural motifs and interaction networks that determine 7 transmembrane (TM) signaling of class B2 GPCRs remain to be elucidated. Comparative sequence–structure analyses of class B2 GPCRs and the recently solved active class B1 structures show that class B2 GPCRs include different elements of the conserved residue motifs that determine class B1 activation. Combined site-directed mutagenesis and molecular dynamics studies were performed to give detailed insights into the role of 7TM interaction networks in signaling of two representative class B2 receptors, ADGRG1 (GPR56) and ADGRL4 (ELTD1). The systematic investigation of class B1/B2 sequence motifs provides consistent structure–function relationships that can be translated to the whole class B2 GPCR family and suggests that class B1 and B2 GPCRs share conserved intramolecular 7TM interactions. This improved understanding in adhesion GPCR structure and constitutive signaling can accelerate drug design campaigns for this chemically unexplored receptor class.

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