Kinetic analysis of fluorescent ligand binding to cell surface receptors: Insights into conformational changes and allosterism in living cells.

Autor: Hill SJ; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK.; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK., Kilpatrick LE; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK.; Division of Bimolecular Science and Medicinal Chemistry, School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham, UK.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Nov; Vol. 181 (21), pp. 4091-4102. Date of Electronic Publication: 2023 Jul 19.
DOI: 10.1111/bph.16185
Abstrakt: Equilibrium binding assays are one of the mainstays of current drug discovery efforts to evaluate the interaction of drugs with receptors in membranes and intact cells. However, in recent years, there has been increased focus on the kinetics of the drug-receptor interaction to gain insight into the lifetime of drug-receptor complexes and the rate of association of a ligand with its receptor. Furthermore, drugs that act on topically distinct sites (allosteric) from those occupied by the endogenous ligand (orthosteric site) can induce conformational changes in the orthosteric binding site leading to changes in the association and/or dissociation rate constants of orthosteric ligands. Conformational changes in the orthosteric ligand binding site can also be induced through interaction with neighbouring accessory proteins and receptor homodimerisation and heterodimerisation. In this review, we provide an overview of the use of fluorescent ligand technologies to interrogate ligand-receptor kinetics in living cells and the novel insights that they can provide into the conformational changes induced by drugs acting on a variety of cell surface receptors including G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and cytokine receptors.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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