Allostery and biased agonism at class b g protein-coupled receptors

Denise Wootten, Laurence J. Miller, Cassandra Koole, Arthur Christopoulos, Patrick M. Sexton

Research output: Contribution to journalReview articlepeer-review

55 Scopus citations


Class B G protein-coupled receptors (GPCRs) respond to paracrine or endocrine peptide hormones involved in control of bone homeostasis, glucose regulation, satiety, and gastro-intestinal function, as well as pain transmission. These receptors are targets for existing drugs that treat osteoporosis, hypercalcaemia, Paget's disease, type II diabetes, and obesity and are being actively pursued as targets for numerous other diseases. Exploitation of class B receptors has been limited by difficulties with small molecule drug discovery and development and an under appreciation of factors governing optimal therapeutic efficacy. Recently, there has been increasing awareness of novel attributes of GPCR function that offer new opportunity for drug development. These include the presence of allosteric binding sites on the receptor that can be exploited as drug binding pockets and the ability of individual drugs to enrich subpopulations of receptor conformations to selectively control signaling, a phenomenon termed biased agonism. In this review, current knowledge of biased signaling and small molecule allostery within class B GPCRs is discussed, highlighting areas that have progressed significantly over the past decade, in addition to those that remain largely unexplored with respect to these phenomena.

Original languageEnglish (US)
Pages (from-to)111-138
Number of pages28
JournalChemical reviews
Issue number1
StatePublished - Jan 11 2017

ASJC Scopus subject areas

  • General Chemistry


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