Importance of the C‐terminal α‐helical structure for glucagon's biological activity

JOHN L. KRSTENANSKY, CHRISTIAN ZECHEL, DEV TRIVEDI, VICTOR J. HRUBY

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The synthetic glucagon analogues [Glu21]glucagon, 2, and [Lys17.18.Glu21]glucagon, 3, were designed using Chou‐Fasman calculations for the purpose of enhancing the probability for the formation of a C‐terminal amphipathic α‐helical conformation. Circular dichroism indicates increased α‐helical content for these analogues in solution relative to glucagon. Analogues 2 and 3 also exhibit a 3‐fold and 5‐fold increase in receptor binding potency, respectively. The adenylate cyclase stimulating potencies of 2 and 3 relative to glucagon are 2.1 and 7 times greater, respectively. Attempts were made at further α‐helical enhancement by further substitutions in the 10–13 region of glucagon. as represented by the glucagon analogues [Phe13,Lys17.18 Glu21]glucagon, 4, and [Phe10.13, Lys17.18,Glu21]glucagon. 5. These latter substitutions resulted in lowered receptor binding and adenylate cyclase potencies for 4 and 5 relative to 3 despite increased α‐helical content in solution as observed by circular dichroism spectroscopy.

Original languageEnglish (US)
Pages (from-to)468-475
Number of pages8
JournalInternational journal of peptide and protein research
Volume32
Issue number6
DOIs
StatePublished - Dec 1988

Keywords

  • biological activity
  • glucagon
  • glucagon analogues
  • α‐helical structure

ASJC Scopus subject areas

  • Biochemistry

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