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Further evidence for a C-terminal structural motif in CCK2 receptor active peptide hormones
- Source :
- Peptides. 28:2211-2222
- Publication Year :
- 2007
- Publisher :
- Elsevier BV, 2007.
-
Abstract
- A comparison of the conformational characteristics of the related hormones [Nle(15)] gastrin-17 and [Tyr(9)-SO(3)] cholecystokinin-15, in membrane-mimetic solutions of dodecylphosphocholine micelles and water, was undertaken using NMR spectroscopy to investigate the possibility of a structural motif responsible for the two hormones common ability to stimulate the CCK(2) receptor. Distance geometry calculations and NOE-restrained molecular dynamics simulations in biphasic solvent boxes of decane and water pointed to the two peptides adopting near identical helical C-terminal configurations, which extended one residue further than their shared pentapeptide sequence of Gly-Trp-Met-Asp-Phe-NH(2). The C-terminal conformation of [Nle(15)] gastrin-17 contained a short alpha-helix spanning the Ala(11)-Trp(14) sequence and an inverse gamma-turn centered on Nle(15) while that of [Tyr(9)-SO(3)] cholecystokinin-15 contained a short 3(10) helix spanning its Met(10) to Met(13) sequence and an inverse gamma-turn centered on Asp(14). Significantly, both the C-terminal helices were found to terminate in type I beta-turns spanning the homologous Gly-Trp-Met-Asp sequences. This finding supports the hypothesis that this structural motif is a necessary condition for CCK(2) receptor activation given that both gastrin and cholecystokinin have been established to follow a membrane-associated pathway to receptor recognition and activation. Comparison of the conformations for the non-homologous C-terminal tyrosyl residues of [Nle(15)] gastrin-17 and [Tyr(9)-SO(3)] cholecystokinin-15 found that they lie on opposite faces of the conserved C-terminal helices. The positioning of this tyrosyl residue is known to be essential for CCK(1) activity and non-essential for CCK(2) activity, pointing to it as a possible differentiator in CCK(1)/CCK(2) receptor selection. The different tyrosyl orientations were retained in molecular models for the [Nle(15)] gastrin-17/CCK(2) receptor and [Tyr(9)-SO(3)] cholecystokinin-15/CCK(1) receptor complexes, highlighting the role of this residue as a likely CCK(1)/CCK(2) receptor differentiator.
- Subjects :
- Models, Molecular
Molecular model
Physiology
Stereochemistry
Phosphorylcholine
Amino Acid Motifs
Molecular Sequence Data
Peptide hormone
digestive system
Biochemistry
Pentapeptide repeat
Protein Structure, Secondary
Cellular and Molecular Neuroscience
Endocrinology
310 helix
Gastrins
Amino Acid Sequence
Receptor
Structural motif
Nuclear Magnetic Resonance, Biomolecular
Cholecystokinin
Chemistry
digestive, oral, and skin physiology
Receptor, Cholecystokinin B
Protein Structure, Tertiary
Cholecystokinin B receptor
hormones, hormone substitutes, and hormone antagonists
Protein Binding
Subjects
Details
- ISSN :
- 01969781
- Volume :
- 28
- Database :
- OpenAIRE
- Journal :
- Peptides
- Accession number :
- edsair.doi.dedup.....49cdd1234fa9186c22510359e68167b8
- Full Text :
- https://doi.org/10.1016/j.peptides.2007.09.008