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Conformational and biological characterization of human parathyroid hormone hPTH(1-34) analogues containing β-amino acid residues in positions 17-19
- Source :
- Biopolymers. 70:534-547
- Publication Year :
- 2003
- Publisher :
- Wiley, 2003.
-
Abstract
- The N-terminal 1-34 fragment of parathyroid hormone (PTH) elicits the full spectrum of bone-related biological activities of the intact native sequences. It has been suggested that the structural elements essential for bioactivity are two helical segments located at the N-terminal and C-terminal sequences, connected by hinges or flexible points around positions 12 and 19. In order to assess the relevance of the local conformation around Gly(18) upon biological function, we synthesized and characterized the following human (h) PTH(1-34) analogues containing beta-amino acid residues: [analogues: see text]. Biological activity and binding affinity of analogue I are one order of magnitude lower than those of the parent compound. In analogue II, both binding affinity and biological activity are partially recovered. Analogues III and V have no binding affinity and very low biological activity. Both bioactivity and binding affinity are partially recovered in analogue IV. The conformational properties of the analogues in aqueous solution containing dodecylphosphocholine micelles were studied by CD, 2D-nuclear magnetic resonance and molecular dynamics calculations. The results confirmed the presence in all analogues of two helical segments located at the N-terminal and C-terminal sequences. The insertion of beta-amino acid residues around position 18 does not cause appreciable conformational differences in the five analogues. The differences in biological activity and binding affinity among the five analogues cannot be related to structural differences in the membrane mimetic environment reported in this study. Our results stress the importance of the side-chain functionalities in the sequence 17-19 for biological function.
- Subjects :
- Circular dichroism
Magnetic Resonance Spectroscopy
Protein Conformation
Chemistry
Stereochemistry
Circular Dichroism
Organic Chemistry
Biophysics
Parathyroid hormone
Sequence (biology)
Biological activity
General Medicine
Nuclear magnetic resonance spectroscopy
Ligands
Biochemistry
Micelle
Peptide Fragments
Biomaterials
Protein structure
Amino Acid Substitution
Parathyroid Hormone
Cyclic AMP
Humans
Two-dimensional nuclear magnetic resonance spectroscopy
Subjects
Details
- ISSN :
- 10970282 and 00063525
- Volume :
- 70
- Database :
- OpenAIRE
- Journal :
- Biopolymers
- Accession number :
- edsair.doi.dedup.....9b0e6c6b3c3621ffa34b3526e607a437