Article thumbnail

Crystal Structure of the PAC1R Extracellular Domain Unifies a Consensus Fold for Hormone Recognition by Class B G-Protein Coupled Receptors

By Shiva Kumar, Augen Pioszak, Chenghai Zhang, Kunchithapadam Swaminathan and H. Eric Xu


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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (1970). A general method applicable to the search for similarities in the amino acid sequence of two proteins.
  2. (2003). A graphical user interface to the CCP4 program suite.
  3. (1990). Arimura A
  4. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.
  5. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function.
  6. (1990). Bindingsites of a novel neuropeptide Pituitary-Adenylate-Cyclase-Activating polypeptide in the Rat-brain and lung.
  7. (2006). Comparative study of the effects of PACAP in young, aging, and castrated males in a rat model of Parkinson’s disease.
  8. (2006). Complexing Receptor Pharmacology.
  9. (2007). Crystal structure of the incretin-bound extracellular domain of a G proteincoupled receptor.
  10. (2008). Crystal Structure of the Ligand-bound Glucagon-like Peptide-1 Receptor Extracellular Domain.
  11. (2001). Electrostatics of nanosystems: Application to microtubules and the ribosome.
  12. (1984). Evidence that Helodermin, a newly extracted peptide from Gila monster venom, is a member of the Secretin VIP PHI family of peptides with an original pattern of biological properties.
  13. (2010). Features and development of Coot.
  14. (1994). Human type-I Pituitary Adenylate-Cyclase Activating Polypeptide Receptor (ADYAP1R) -Localization to chromosome band 7P14 and integration into the cytogenetic, physical, and genetic-map of chromosome-7.
  15. (1998). Inactivating mutation in the human parathyroid hormone receptor type 1 gene in Blomstrand chondrodysplasia.
  16. (1989). Isolation of a novel-38 residue-hypothalamic polypeptide which stimulates AdenylateCyclase in Pituitary-cells.
  17. (2005). Mechanisms of peptide and nonpeptide ligand binding to class B G-protein coupled receptors.
  18. (2008). Molecular recognition of parathyroid hormone by its G protein-coupled receptor.
  19. (2008). Molecular recognition of parathyroid hormone by its G protein-coupled receptor. Molecular recognition of parathyroid hormone by its G protein-coupled receptor 105:
  20. (2004). NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor.
  21. (2000). PAC1 receptor-deficient mice display impaired insulinotropic response to glucose and reduced glucose tolerance.
  22. (2006). PAC1 receptor: emerging target for septic shock therapy.
  23. (1997). PACAP type I receptor activation promotes cerebellar neuron survival through the cAMP/PKA signaling pathway.
  24. (2009). Passing the baton in class B GPCRs: peptide hormone activation via helix induction?
  25. (2007). Phaser crystallographic software.
  26. (1996). Pituitary adenylate cyclase activating polypeptide prevents apoptosis in cultured cerebellar granule neurons.
  27. (1996). Pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP/vasoactive intestinal polypeptide receptors: Actions on the anterior pituitary gland.
  28. (1995). Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) stimulates Adenylyl-Cyclase and Phospholipase-C activity in Rat cerebellar neuroblasts.
  29. (2009). Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery.
  30. (2011). Posttraumatic stress disorder is associated with PACAP and the PAC1 receptor.
  31. (1990). Presence of highly selective receptors for PACAP (Pituitary Adenylate-Cyclase Activating Peptide) in membranes from the Rat pancreatic acinar cell-line AR-4-2J.
  32. (1997). Processing of X-ray diffraction data collected in oscillation mode. Macromolecular Crystallography, Pt A.
  33. (1993). PROCHECK -A program to check the sterechemical quality of protein structures.
  34. (1997). Refinement of macromolecular structures by the maximum-likelihood method.
  35. (1997). Regulation of apopotosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain.
  36. (2008). Role of pituitary adenylate cyclase-activating polypeptide in the pancreatic endocrine system.
  37. (2007). Solution structure and mutational analysis of pituitary adenylate cyclase-activating polypeptide binding to the extracellular domain of PAC1-RS.
  38. (2010). Structural basis for hormone recognition by the human CRFR2alpha G protein-coupled receptor.
  39. (2004). SuperPose: a simple server for sophisticated structural superposition.
  40. (1994). The CCP4 suite- Programs for protein crystallogrpahy.
  41. (1990). The novel VIP-like hupothalamic polypeptide PACAP interacts with high-affinity receptors in the human neuroblastoma cell-line NB-OK.
  42. (2000). The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily.
  43. (1999). VIP and PACAP: very important in pain?