The Nociceptin Pharmacophore Site for Opioid Receptor Binding Derived from the NMR Structure and Bioactivity Relationships

Nociceptin, a 17 amino acid opioid-like peptide that has an inhibitory effect on synaptic transmission in the nervous system, is involved in learning, memory, attention, and emotion and is also implicated in the perception of pain and visual, auditory, and olfactory functions. In this study, we inve...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2005-03, Vol.280 (9), p.8134-8142
Main Authors: Orsini, Michael J, Nesmelova, Irina, Young, Helen C, Hargittai, Balazs, Beavers, Mary Pat, Liu, Jingchun, Connolly, Peter J, Middleton, Steven A, Mayo, Kevin H
Format: Article
Language:English
Subjects:
Alanine - chemistry
Amino Acid Sequence
Binding Sites
Binding, Competitive
Calcium - chemistry
Cell Line
Cell Membrane - metabolism
Databases as Topic
Dose-Response Relationship, Drug
Drug Design
Humans
Kinetics
Magnetic Resonance Spectroscopy - methods
Micelles
Models, Molecular
Molecular Sequence Data
Nociceptin
Nociceptin Receptor
Nucleic Acid Conformation
Opioid Peptides - chemistry
Opioid Peptides - metabolism
Peptides - chemistry
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Receptors, Opioid - chemistry
Sodium Dodecyl Sulfate - chemistry
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Nociceptin, a 17 amino acid opioid-like peptide that has an inhibitory effect on synaptic transmission in the nervous system, is involved in learning, memory, attention, and emotion and is also implicated in the perception of pain and visual, auditory, and olfactory functions. In this study, we investigated the NMR solution structure of nociceptin in membrane-like environments (trifluoroethanol and SDS micelles) and found it to have a relatively stable helix conformation from residues 4–17 with functionally important N-terminal residues being folded aperidoically on top of the helix. In functional assays for receptor binding and calcium flux, alanine-scanning variants of nociceptin indicated that functionally important residues generally followed helix periodicity, consistent with the NMR structural model. Structure-activity relationships allowed identification of pharmacophore sites that were used in small molecule data base searches, affording hits with demonstrated nociceptin receptor binding affinities.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M406405200