Crystal structure of the PAC1R extracellular domain unifies a consensus fold for hormone recognition by class B G-protein coupled receptors

PLoS One. 2011;6(5):e19682. doi: 10.1371/journal.pone.0019682. Epub 2011 May 19.

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the PACAP/glucagon family of peptide hormones, which controls many physiological functions in the immune, nervous, endocrine, and muscular systems. It activates adenylate cyclase by binding to its receptor, PAC1R, a member of class B G-protein coupled receptors (GPCR). Crystal structures of a number of Class B GPCR extracellular domains (ECD) bound to their respective peptide hormones have revealed a consensus mechanism of hormone binding. However, the mechanism of how PACAP binds to its receptor remains controversial as an NMR structure of the PAC1R ECD/PACAP complex reveals a different topology of the ECD and a distinct mode of ligand recognition. Here we report a 1.9 Å crystal structure of the PAC1R ECD, which adopts the same fold as commonly observed for other members of Class B GPCR. Binding studies and cell-based assays with alanine-scanned peptides and mutated receptor support a model that PAC1R uses the same conserved fold of Class B GPCR ECD for PACAP binding, thus unifying the consensus mechanism of hormone binding for this family of receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Consensus Sequence
  • Crystallography, X-Ray
  • Cyclic AMP / metabolism
  • Extracellular Matrix / metabolism
  • Hormones / metabolism*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism*
  • Protein Conformation
  • Protein Folding*
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / chemistry*
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / metabolism*

Substances

  • ADCYAP1 protein, human
  • Hormones
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Receptors, G-Protein-Coupled
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
  • Cyclic AMP