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  • Title: Role of the phenylalanine B25 side chain in directing insulin interaction with its receptor. Steric and conformational effects.
    Author: Nakagawa SH, Tager HS.
    Journal: J Biol Chem; 1986 Jun 05; 261(16):7332-41. PubMed ID: 3519607.
    Abstract:
    To gain an understanding of the causes of decreased biological activity in insulins bearing amino acid substitutions at position B25 and the importance of the PheB25 side chain in directing hormone-receptor interactions, we have prepared a variety of insulin analogs and have studied both their interactions with isolated canine hepatocytes and their abilities to stimulate glucose oxidation by isolated rat adipocytes. The semisynthetic analogs fall into three structural classes: (a) analogs in which the COOH-terminal 5, 6, or 7 residues of the insulin B-chain have been deleted, but in which the COOH-terminal residue of the B-chain has been derivatized by alpha-carboxamidation; (b) analogs in which PheB25 has been replaced by unnatural aromatic or natural L-amino acids; and (c) analogs in which the COOH-terminal 5 residues of the insulin B-chain have been deleted and in which residue B25 has been replaced by selected alpha-carboxamidated amino acids. Our results showed that (a) insulin residues B26-B30 can be deleted without decrease in biological potency, whereas deletion of residues B25-B30 and B24-B30 causes a marked and cumulative decrease in potency; (b) replacement of PheB25 in insulin by Leu or Ser results in analogs with biological potency even less than that observed when residues B25-B30 are deleted; (c) the side chain bulk of naphthyl(1)-alanine or naphthyl(2)-alanine at position B25 is well tolerated during insulin interactions with receptor, whereas that of homophenylalanine is not; and (d) the decreased biological potency attending substitution of insulin PheB25 by Ala, Ser, Leu, or homophenylalanine is reversed, in part or in total, by deletion of COOH-terminal residues B26-B30. Additional experiments showed that the rate of dissociation of receptor-bound 125I-labeled insulin from isolated hepatocytes is enhanced by incubating cells with insulin or [naphthyl(2)-alanineB25]insulin, but not with analogs in which PheB25 is replaced by serine, leucine, or homophenylalanine; deletion of residues B26-B30, however, results in analogs that enhance the rate of dissociation of receptor-bound insulin in all cases studied. We conclude that (a) steric hindrance involving the COOH-terminal domain of the B chain plays a major role in directing the interaction of insulin with its receptor; (b) the initial negative effect of this domain is reversed upon the filling of a site reflecting interaction of the receptor and the beta-aromatic ring of the PheB25 side chain.(ABSTRACT TRUNCATED AT 400 WORDS)
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