TAILIEUCHUNG - Báo cáo Y học: Relaxin-like bioactivity of ovine Insulin 3 (INSL3) analogues

Relaxin is an insulin-like peptide consisting of two separate chains (A and B) joined by two inter- and one intrachain disulfide bonds. Binding to its receptor requires an Arg–X– X–X–Arg–X–X–Ile motif in the B-chain. A relatedmember of the insulin superfamily, INSL3, has a tertiary structure that is predicted to be similar to relaxin. It also possesses an Arg–X–X–X–Arg motif within its B-chain, although this is displaced by four amino acids towards the C-terminus from the corresponding position within relaxin | Eur. J. Biochem. 269 6287-6293 2002 FEBS 2002 doi Relaxin-like bioactivity of ovine Insulin 3 INSL3 analogues Antonia A Claasz1. Courtnev P. Bond2 Ross A Bathgate1. Laszlo Otvos Jr3 Nicola F. Dawson1 BB B Fl B Roger Jb Summers2 Geoffrey Wb Tregear1 and John Db Wade1 1 Howard Florey Institute University of Melbourne Victoria Australia department of Pharmacology Monash University Victoria Australia 3 The Wistar Institute Philadelphia USA Relaxin is an insulin-like peptide consisting of two separate chains A and B joined by two inter- and one intrachain disulfide bonds. Binding to its receptor requires an Arg-X-X-X-Arg-X-X-Ile motif in the B-chain. A related member of the insulin superfamily INSL3 has a tertiary structure that is predicted to be similar to relaxin. It also possesses an Arg-X-X-X-Arg motif within its B-chain although this is displaced by four amino acids towards the C-terminus from the corresponding position within relaxin. We have previously shown that synthetic INSL3 itself does not display relaxin-like activity although analogue Analogue A with an introduced arginine residue in the B-chain giving it an Arg cassette in the exact relaxin position does possess weak activity. In order to identify further the structural features that impart relaxin function solid phase peptide synthesis was used to prepare three additional analogues for bioassay. Each of these contained point substitutions within the arginine cassette. Analogue D contained the full human relaxin binding cassette Analogue G consisted of the native INSL3 sequence containing an Arg to Ala substitution and Analogue E was a further modification of Analogue A with the same substitution. Each analogue was fully chemically characterized by a number of criteria. Detailed circular dichrosim spectroscopy analyses showed that the changes caused little alteration of secondary structure and hence overall conformation. However each analogue displayed only weak .

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