Relevance of G protein-coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation

Lopez-Balastegui, Marta; Stepniewski, Tomasz Maciej, 1988-; Kogut-Günthel, Małgorzata M.; Di Pizio, Antonella; Rosenkilde, Mette Marie; Mao, Jiafei; Selent, Jana

doi:http://dx.doi.org/10.1111/bph.16495

Relevance of G protein-coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation

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Lopez-Balastegui M, Stepniewski TM, Kogut-Günthel MM, Di Pizio A, Rosenkilde MM, Mao J, et al. Relevance of G protein-coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation. Br J Pharmacol. 2025 Jul;182(14):3211-24. DOI: 10.1111/bph.16495

Abstract

G protein-coupled receptors (GPCRs) are one of the major drug targets. In recent years, computational drug design for GPCRs has mainly focused on static structures obtained through X-ray crystallography, cryogenic electron microscopy (cryo-EM) or in silico modelling as a starting point for virtual screening campaigns. However, GPCRs are highly flexible entities with the ability to adopt different conformational states that elicit different physiological responses. Including this knowledge in the drug discovery pipeline can help to tailor novel conformation-specific drugs with an improved therapeutic profile. In this review, we outline our current knowledge about GPCR dynamics that is relevant for receptor activation, signalling bias and allosteric modulation. Ultimately, we highlight new technological implementations such as time-resolved X-ray crystallography and cryo-EM as well as computational algorithms that can contribute to a more comprehensive understanding of receptor dynamics and its relevance for GPCR functionality.