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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
Author(s) -
Schievano E.,
Mammi S.,
Carretta E.,
Fiori N.,
Corich M.,
Bisello A.,
Rosenblatt M.,
Chorev M.,
Peggion E.
Publication year - 2003
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.10508
Subject(s) - chemistry , stereochemistry , biological activity , parathyroid hormone , amino acid , peptide , peptide sequence , biochemistry , in vitro , calcium , organic chemistry , gene
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 β‐amino acid residues: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 β‐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. © 2003 Wiley Periodicals, Inc. Biopolymers 70: 534–547, 2003