Structure of Class B GPCRs: new horizons for drug discovery

Br J Pharmacol. 2014 Jul;171(13):3132-45. doi: 10.1111/bph.12689.


Class B GPCRs of the secretin family are important drug targets in many human diseases including diabetes, neurodegeneration, cardiovascular disease and psychiatric disorders. X-ray crystal structures for the glucagon receptor and corticotropin-releasing factor receptor 1 have now been published. In this review, we analyse the new structures and how they compare with each other and with Class A and F receptors. We also consider the differences in druggability and possible similarity in the activation mechanisms. Finally, we discuss the potential for the design of small-molecule modulators for these important targets in drug discovery. This new structural insight allows, for the first time, structure-based drug design methods to be applied to Class B GPCRs.

Keywords: CRF1 receptor; Class B; GPCR; GPCR molecular signature; HHM; druggability; glucagon receptor; smoothened receptor.

Publication types

  • Review

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Drug Design*
  • Drug Discovery / methods
  • Humans
  • Molecular Targeted Therapy
  • Protein Conformation
  • Receptors, Corticotropin-Releasing Hormone / chemistry
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / drug effects
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Gastrointestinal Hormone / chemistry*
  • Receptors, Gastrointestinal Hormone / drug effects
  • Receptors, Gastrointestinal Hormone / metabolism
  • Receptors, Glucagon / chemistry


  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, G-Protein-Coupled
  • Receptors, Gastrointestinal Hormone
  • Receptors, Glucagon
  • secretin receptor
  • CRF receptor type 1