Solution structure and mutational analysis of pituitary adenylate cyclase-activating polypeptide binding to the extracellular domain of PAC1-R S
| Autor: | Paul L. Richardson, Victoria E. Scott, Marie E. Uchic, Larry Solomon, Edward T. Olejniczak, Karl A. Walter, Rachel Davis-Taber, Danying Song, Chaohong Sun, Leo W. Barrett, Ana Pereda-Lopez, Philip J. Hajduk, Marc R. Lake |
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| Rok vydání: | 2007 |
| Předmět: |
Molecular Sequence Data
Vasoactive intestinal peptide Peptide binding Peptide Biology Receptors Corticotropin-Releasing Hormone Protein Structure Secondary Mice Extracellular Animals Humans Amino Acid Sequence Receptor Peptide sequence chemistry.chemical_classification Multidisciplinary C-terminus Biological Sciences Protein Structure Tertiary Cell biology Solutions N-terminus Biochemistry chemistry Mutation Pituitary Adenylate Cyclase-Activating Polypeptide Receptors Pituitary Adenylate Cyclase-Activating Polypeptide Type I |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:7875-7880 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | The pituitary adenylate cyclase-activating polypeptide (PACAP) receptor is a class II G protein-coupled receptor that contributes to many different cellular functions including neurotransmission, neuronal survival, and synaptic plasticity. The solution structure of the potent antagonist PACAP (residues 6′–38′) complexed to the N-terminal extracellular (EC) domain of the human splice variant hPAC1-R-short (hPAC1-R S ) was determined by NMR. The PACAP peptide adopts a helical conformation when bound to hPAC1-R S with a bend at residue A18′ and makes extensive hydrophobic and electrostatic interactions along the exposed β-sheet and interconnecting loops of the N-terminal EC domain. Mutagenesis data on both the peptide and the receptor delineate the critical interactions between the C terminus of the peptide and the C terminus of the EC domain that define the high affinity and specificity of hormone binding to hPAC1-R S . These results present a structural basis for hPAC1-R S selectivity for PACAP versus the vasoactive intestinal peptide and also differentiate PACAP residues involved in binding to the N-terminal extracellular domain versus other parts of the full-length hPAC1-R S receptor. The structural, mutational, and binding data are consistent with a model for peptide binding in which the C terminus of the peptide hormone interacts almost exclusively with the N-terminal EC domain, whereas the central region makes contacts to both the N-terminal and other extracellular parts of the receptor, ultimately positioning the N terminus of the peptide to contact the transmembrane region and result in receptor activation. |
| Databáze: | OpenAIRE |
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