FlAsH-walk mapping: a step-by-step approach to GPCR conformation cartography


Competition: EXPLORE Program 2011
Funding: $300,000 / 2 years
Début : December 2011


A library for G-protein coupled receptors sensors will be generated to analyze the conformational mapping of receptor dynamics upon binding and activation.


This project aims at generating a library for G-protein coupled receptors sensors to analyze the conformational mapping of receptor dynamics upon binding and activation.

G protein-coupled receptors (GPCRs) are the largest target class for approved drugs. Identification of new drug candidates has relied exclusively on high-throughput assays which track binding properties and are limited to a restricted number of signaling pathways. GPCRs however are highly dynamic proteins that undergo numerous conformational changes upon receptor association with ligands and related protein partners. Use of such drug induced conformational changes has in general been overlooked as an approach to enhance efficient discovery of novel drugs for GPCRs due to the difficulty in adapting structural approaches to high-throughput screening (HTS).

Dr. Hébert and his team will pursue the use of receptor dynamics from diverse conformational vantage points to better understand the interactions between drugs and their target GPCRs, thereby enabling the design of more effective GPCR-based therapeutics. Specifically, they are developing and validating a new method to establish conformational signatures, or FlAsH-walk maps. This focuses on the various conformations that GPCRs can adopt following ligand binding which leads to activation of their distinct signaling pathways. To this end, in vitro assays will be established based on resonance energy transfer (BRET or FRET) to analyze conformational dynamics of receptor activation upon ligand binding and engagement of G proteins and other effectors. These interactions between GPCRs and their partners can be measured in real-time allowing cell-based assays to be used in HTS modes. Recent progress in the project shows that the engineered tags are well tolerated functionally by the target receptors. These tags provide distinct measures of conformation depending on where they are placed in the receptors when used as BRET acceptors with interacting proteins.

Impact on the drug discovery process

  • Novel GPCR-based therapeutics identified through drug induced conformational activation of distinct signaling pathways.

Terry Hébert

McGill University


Sylvain Chemtob
Hôpital Sainte-Justine

Audrey Claing et William Lubell
Université de Montréal

Stéphane Laporte
MUHC Royal Victoria Hospital


Arjan Snijder
Associate Principal Scientist,
AstraZeneca Discovery R&D, Discovery Sciences, Mölndal, Sweden

Thomas J. Rimele
Senior Director Cellular Biochemistry,
GlaxoSmithKline Inc., RTP, NC, USA

Christian C. Felder
Research Scientist, Neuroscience,
Neuroscience Eli Lilly & Co. USA