Structural insight to mutation effects uncover a common allosteric site in class C GPCRs

Kasper Harpsøe; Michael W Boesgaard; Christian Munk; Hans Bräuner-Osborne; David E Gloriam

doi:10.1093/bioinformatics/btw784

Structural insight to mutation effects uncover a common allosteric site in class C GPCRs

Kasper Harpsøe, Michael W Boesgaard, Christian Munk, Hans Bräuner-Osborne, David E Gloriam

8 Citations (Scopus)

77 Downloads (Pure)

Abstract

Motivation: Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry. Combining pharmacological site-directed mutagenesis data with the recent class C GPCR experimental structures will provide a foundation for rational design of new therapeutics. Results: We uncover one common site for both positive and negative modulators with different amino acid layouts that can be utilized to obtain selectivity. Additionally, we show a large potential for structure-based modulator design, especially for four orphan receptors with high similarity to the crystal structures.

Original language	English
Article number	btw784
Journal	Bioinformatics (Oxford, England)
Volume	33
Issue number	8
Pages (from-to)	1116-1120
Number of pages	5
ISSN	1367-4803
DOIs	https://doi.org/10.1093/bioinformatics/btw784
Publication status	Published - 15 Apr 2017

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title = "Structural insight to mutation effects uncover a common allosteric site in class C GPCRs",

abstract = "Motivation: Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry. Combining pharmacological site-directed mutagenesis data with the recent class C GPCR experimental structures will provide a foundation for rational design of new therapeutics. Results: We uncover one common site for both positive and negative modulators with different amino acid layouts that can be utilized to obtain selectivity. Additionally, we show a large potential for structure-based modulator design, especially for four orphan receptors with high similarity to the crystal structures.",

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AU - Harpsøe, Kasper

AU - Boesgaard, Michael W

AU - Munk, Christian

AU - Bräuner-Osborne, Hans

AU - Gloriam, David E

PY - 2017/4/15

Y1 - 2017/4/15

N2 - Motivation: Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry. Combining pharmacological site-directed mutagenesis data with the recent class C GPCR experimental structures will provide a foundation for rational design of new therapeutics. Results: We uncover one common site for both positive and negative modulators with different amino acid layouts that can be utilized to obtain selectivity. Additionally, we show a large potential for structure-based modulator design, especially for four orphan receptors with high similarity to the crystal structures.

AB - Motivation: Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry. Combining pharmacological site-directed mutagenesis data with the recent class C GPCR experimental structures will provide a foundation for rational design of new therapeutics. Results: We uncover one common site for both positive and negative modulators with different amino acid layouts that can be utilized to obtain selectivity. Additionally, we show a large potential for structure-based modulator design, especially for four orphan receptors with high similarity to the crystal structures.

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Structural insight to mutation effects uncover a common allosteric site in class C GPCRs

Abstract

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