Design of analogues of parathyroid hormone: A conformational approach
Journal of Protein Chemistry, ISSN: 0277-8033, Vol: 4, Issue: 6, Page: 391-406
1985
- 9Citations
- 1Captures
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Article Description
An approach to the design of peptide-hormone analogues in which amino acid substitutions are based on predicted effects on secondary structure was investigated. The structural requirements for parathyroid-hormone (PTH) action are distinct from the determinants necessary for receptor binding alone without subsequent activation of adenylate cyclase. Two analogues of PTH containing substitutions in the principal binding domain of PTH, the region 25-34, were synthesized by the solid-phase method and evaluated for bioactivity. The sequence 25-34 was predicted to have nearly equal conformational potential for both α-helix and β-sheet using Chou and Fasman parameters. A previously studied analogue, [Tyr]bPTH(1-34) amide, containing substitutions in this region, was more active than was bPTH-(1-34). The substitution of tyrosine for phenylalanine at position 34 in this analogue is predicted to promote β-sheet conformation. The analogues [Ile, Tyr, Tyr]bPTH-(1-34) amide and [Arg, Tyr]bPTH-(1-34) amide each contain substitutions predicted to further enhance or stabilize β-sheet formation. The solution conformation of these analogues, determined by circular dichroism studies in an aqueous buffer and an organic solvent, indicated promotion of β-sheet secondary structural content in both analogues in a hydrophobic environment chosen to simulate that of the interaction of the peptide and the membrane receptor. In contrast, the native sequence lacks β-structure. Biological activity of these analogues in the rat renal adenylate cyclase assay in vitro and binding affinity in a radioreceptor assay were threefold those of unsubstituted PTH-(1-34). Peptide analogue design based on conformational prediction, rather than substitution of primary structure alone, offers an attractive alternative approach to the development of hormone analogues and antagonists. © 1985 Plenum Publishing Corporation.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0022295344&origin=inward; http://dx.doi.org/10.1007/bf01025179; https://link.springer.com/10.1007/BF01025179; http://link.springer.com/10.1007/BF01025179; http://www.springerlink.com/index/pdf/10.1007/BF01025179; http://www.springerlink.com/index/10.1007/BF01025179; https://dx.doi.org/10.1007/bf01025179; https://link.springer.com/article/10.1007/BF01025179
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