title: Three-chain insulin analogs demonstrate the importance of insulin secondary structure to bioactivity.
abstract: This report describes the chemical synthesis and biological characterization of novel three-chain insulin analogs with a destabilized secondary structure. The analogs, obtained by chemical synthesis via a single-chain precursor and selective enzymatic digestion, were used to investigate the role of the highly conserved 'insulin fold'. Biological characterization through in vitro biochemical signaling showed extremely low activity at each insulin receptor when compared with native insulin. We conclude that the 'insulin fold' is a structural foundation that supports insulin biological action.
authors: Department of Chemistry, Indiana University, Bloomington, IN, 47405, USA.
authors: Fangzhou
authors: F
authors: Wu
authors: Joseph R
authors: JR
authors: Chabenne
authors: Vasily M
authors: VM
authors: Gelfanov
authors: John P
authors: JP
authors: Mayer
authors: Richard D
authors: RD
authors: DiMarchi
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D060327:Solid-Phase Synthesis Techniques; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000737:chemistry
chemical_list: D015703:Antigens, CD; D007328:Insulin; C435941:INSR protein, human; D011972:Receptor, Insulin; D014357:Trypsin; D008666:Metalloendopeptidases; C039830:peptidyl-Lys metalloendopeptidase
keywords: enzyme-assisted synthesis; insulin; insulin receptor interaction; single-chain insulin analogs