Evidence that interaction between conserved residues in transmembrane helices 2, 3, and 7 are crucial for human VPAC1 receptor activation

Anton O Chugunov, John Simms, David R Poyner, Yves Dehouck, Marianne Rooman, Dimitri Gilis, Ingrid Langer

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


The VPAC(1) receptor belongs to family B of G protein-coupled receptors (GPCR-B) and is activated upon binding of the vasoactive intestinal peptide (VIP). Despite the recent determination of the structure of the N terminus of several members of this receptor family, little is known about the structure of the transmembrane (TM) region and about the molecular mechanisms leading to activation. In the present study, we designed a new structural model of the TM domain and combined it with experimental mutagenesis experiments to investigate the interaction network that governs ligand binding and receptor activation. Our results suggest that this network involves the cluster of residues Arg(188) in TM2, Gln(380) in TM7, and Asn(229) in TM3. This cluster is expected to be altered upon VIP binding, because Arg(188) has been shown previously to interact with Asp(3) of VIP. Several point mutations at positions 188, 229, and 380 were experimentally characterized and were shown to severely affect VIP binding and/or VIP-mediated cAMP production. Double mutants built from reciprocal residue exchanges exhibit strong cooperative or anticooperative effects, thereby indicating the spatial proximity of residues Arg(188), Gln(380), and Asn(229). Because these residues are highly conserved in the GPCR-B family, they can moreover be expected to have a general role in mediating function.

Original languageEnglish
Pages (from-to)394-401
Number of pages8
JournalMolecular Pharmacology
Issue number3
Publication statusPublished - Sept 2010


  • Animals
  • Asparagine
  • Cellular Structures
  • Cricetinae
  • Humans
  • Mutagenesis
  • Protein Structure, Secondary
  • Receptors, G-Protein-Coupled
  • Receptors, Vasoactive Intestinal Polypeptide, Type I
  • Vasoactive Intestinal Peptide
  • Journal Article
  • Research Support, Non-U.S. Gov't


Dive into the research topics of 'Evidence that interaction between conserved residues in transmembrane helices 2, 3, and 7 are crucial for human VPAC1 receptor activation'. Together they form a unique fingerprint.

Cite this