G-protein-coupled receptor allosterism: the promise and the problem(s)

• Published in: Biochemical Society transactions Vol. 32; no. Pt 5; p. 873
• Main Authors: Christopoulos, A, May, L T, Avlani, V A, Sexton, P M
• Format: Journal Article
• Language: English
• Published: England 01-11-2004
• Subjects: Alcuronium - pharmacology; Allosteric Site; Animals; Binding Sites; Dose-Response Relationship, Drug; Drug Design; Humans; Kinetics; Ligands; Models, Chemical; Protein Binding; Protein Structure, Tertiary; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Signal Transduction
• ISSN: 0300-5127
• DOI: 10.1042/BST0320873

Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more 'physiological' regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validation of allosteric ligands.