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Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform

151 Pages Posted: 15 May 2020 Sneak Peek Status: Under Review

See all articles by Charlotte Avet

Charlotte Avet

University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine

Arturo Mancini

Domain Therapeutics North America

Billy Breton

Domain Therapeutics North America

Christian Le Gouill

University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine

Alexander Hauser

University of Copenhagen, Department of Drug Design and Pharmacology

Claire Normand

Domain Therapeutics North America

Hiroyuki Kobayashi

University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine

Florence Gross

Domain Therapeutics North America

Mireille Hogue

University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine

Viktoriya Lukasheva

University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine

Sandra Morissette

Domain Therapeutics North America

Eric Fauman

Pfizer Worldwide Research, Internal Medicine Research Unit

Jean-Philippe Fortin

Pfizer, Inc. - Pfizer Global Research & Development

Stéphane Schann

Domain Therapeutics

Xavier Leroy

Domain Therapeutics

David E. Gloriam

University of Copenhagen, Department of Drug Design and Pharmacology

Michel Bouvier

University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine

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Abstract

The ability of individual G protein-coupled receptors (GPCR) to engage multiple signaling pathways opens opportunities for the development of better drugs. This requires new knowledge and tools to determine the G protein subtypes and barrestins engaged by a given receptor. Here, we used a new BRET-based effector membrane translocation assay (EMTA) that monitors activation of each Gα protein through the recruitment of selective G protein effectors and βarrestins to the plasma membrane. Profiling of 100 therapeutically relevant GPCR revealed a great diversity of coupling profiles with some receptors displaying exquisite selectivity, whereas others promiscuitely engage all four G protein families. Comparison with existing datasets points to commonalities but also to critical differences between studies. Combining a biosensor subset allowed detecting activity of nearly all GPCR thus providing a new tool for safety screens and systems pharmacology. Overall, this work describes unique resources for studying GPCR function and drug discovery.

Suggested Citation

Avet, Charlotte and Mancini, Arturo and Breton, Billy and Le Gouill, Christian and Hauser, Alexander and Normand, Claire and Kobayashi, Hiroyuki and Gross, Florence and Hogue, Mireille and Lukasheva, Viktoriya and Morissette, Sandra and Fauman, Eric and Fortin, Jean-Philippe and Schann, Stéphane and Leroy, Xavier and Gloriam, David E. and Bouvier, Michel, Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform. Available at SSRN: https://ssrn.com/abstract=3586569 or http://dx.doi.org/10.2139/ssrn.3586569
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Charlotte Avet

University of Montreal - Institute for Research in Immunology and Cancer (IRIC) ( email )

2900 Édouard-Montpetit Blvd.
Montreal, Quebec H3T 1J4
Canada

University of Montreal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Arturo Mancini

Domain Therapeutics North America ( email )

No Address Available
United States

Billy Breton

Domain Therapeutics North America ( email )

No Address Available
United States

Christian Le Gouill

University of Montreal - Institute for Research in Immunology and Cancer (IRIC) ( email )

2900 Édouard-Montpetit Blvd.
Montreal, Quebec H3T 1J4
Canada

University of Montreal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Alexander Hauser

University of Copenhagen, Department of Drug Design and Pharmacology ( email )

No Address Available
United States

Claire Normand

Domain Therapeutics North America ( email )

No Address Available
United States

Hiroyuki Kobayashi

University of Montreal - Institute for Research in Immunology and Cancer (IRIC) ( email )

2900 Édouard-Montpetit Blvd.
Montreal, Quebec H3T 1J4
Canada

University of Montreal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Florence Gross

Domain Therapeutics North America ( email )

No Address Available
United States

Mireille Hogue

University of Montreal - Institute for Research in Immunology and Cancer (IRIC) ( email )

2900 Édouard-Montpetit Blvd.
Montreal, Quebec H3T 1J4
Canada

University of Montreal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Viktoriya Lukasheva

University of Montreal - Institute for Research in Immunology and Cancer (IRIC) ( email )

2900 Édouard-Montpetit Blvd.
Montreal, Quebec H3T 1J4
Canada

University of Montreal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

Sandra Morissette

Domain Therapeutics North America ( email )

No Address Available
United States

Eric Fauman

Pfizer Worldwide Research, Internal Medicine Research Unit ( email )

No Address Available
United States

Jean-Philippe Fortin

Pfizer, Inc. - Pfizer Global Research & Development ( email )

Eastern Point Road
Groton, CT 06340
United States

Stéphane Schann

Domain Therapeutics ( email )

No Address Available
United States

Xavier Leroy

Domain Therapeutics ( email )

No Address Available
United States

David E. Gloriam

University of Copenhagen, Department of Drug Design and Pharmacology ( email )

No Address Available
United States

Michel Bouvier (Contact Author)

University of Montreal - Institute for Research in Immunology and Cancer (IRIC) ( email )

2900 Édouard-Montpetit Blvd.
Montreal, Quebec H3T 1J4
Canada

University of Montreal - Department of Biochemistry and Molecular Medicine ( email )

2900 Boulevard Edouard-Montpetit
Montréal, Québec H3T 1J4
Canada

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