Disposition of the phenylalanine B25 side chain during insulin-receptor and insulin-insulin interactions

Raghu Mirmira, Howard S. Tager

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

By the semisynthesis of both full-length insulin analogues and their des-pentapeptide-(B26-B30)-α-carboxamide counterparts, we have examined the importance of the electronic character and bulk of the position B25 side chain both in directing insulin interaction with its receptor on isolated canine hepatocytes and in determining the ability of insulin to self-associate in solution. Analogues include those in which PheB25 was replaced by cyclohexyl-Ala; Tyr; p-nitro-, p-fluoro- p-iodo- or p-amino-Phe; or p-amino-Phe in which the aromatic amino function had been acylated by the acetyl, hexanoyl, decanoyl, or 1-adamantanoyl group. Our findings identify that (a) the β-aromatic side chain at position B25 is indeed critical for high-affinity ligand-receptor interactions, (b) neither electron withdrawal from nor electron donation to the β-aromatic ring perturbs ligand-receptor interactions in major ways, (c) considerable lattitude is allowed the placement of linear or polycyclic apolar mass at the para position in p-amino-PheB25-substituted analogues with respect both to receptor binding affinity and to biological activity in vivo, and (d) para apolar mass at position B25 is readily accommodated during the self-association of insulin monomers, as assessed by analytical tyrosine radioiodination and spectroscopic analysis of analogue complexes with Co2+ and Co3+. These findings are discussed in terms of a model for insulin-receptor interactions at the cell membrane in which the position B25 side chain defines the edge of intermolecular contact.

Original languageEnglish (US)
Pages (from-to)8222-8229
Number of pages8
JournalBiochemistry
Volume30
Issue number33
StatePublished - 1991
Externally publishedYes

Fingerprint

Insulin Receptor
Phenylalanine
Insulin
Electrons
Ligands
Spectroscopic analysis
Cell membranes
Bioactivity
Tyrosine
Canidae
Hepatocytes
Monomers
Cell Membrane
Association reactions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Disposition of the phenylalanine B25 side chain during insulin-receptor and insulin-insulin interactions. / Mirmira, Raghu; Tager, Howard S.

In: Biochemistry, Vol. 30, No. 33, 1991, p. 8222-8229.

Research output: Contribution to journalArticle

@article{b6dae44736664e6f9153ae1b5ee5e17f,
title = "Disposition of the phenylalanine B25 side chain during insulin-receptor and insulin-insulin interactions",
abstract = "By the semisynthesis of both full-length insulin analogues and their des-pentapeptide-(B26-B30)-α-carboxamide counterparts, we have examined the importance of the electronic character and bulk of the position B25 side chain both in directing insulin interaction with its receptor on isolated canine hepatocytes and in determining the ability of insulin to self-associate in solution. Analogues include those in which PheB25 was replaced by cyclohexyl-Ala; Tyr; p-nitro-, p-fluoro- p-iodo- or p-amino-Phe; or p-amino-Phe in which the aromatic amino function had been acylated by the acetyl, hexanoyl, decanoyl, or 1-adamantanoyl group. Our findings identify that (a) the β-aromatic side chain at position B25 is indeed critical for high-affinity ligand-receptor interactions, (b) neither electron withdrawal from nor electron donation to the β-aromatic ring perturbs ligand-receptor interactions in major ways, (c) considerable lattitude is allowed the placement of linear or polycyclic apolar mass at the para position in p-amino-PheB25-substituted analogues with respect both to receptor binding affinity and to biological activity in vivo, and (d) para apolar mass at position B25 is readily accommodated during the self-association of insulin monomers, as assessed by analytical tyrosine radioiodination and spectroscopic analysis of analogue complexes with Co2+ and Co3+. These findings are discussed in terms of a model for insulin-receptor interactions at the cell membrane in which the position B25 side chain defines the edge of intermolecular contact.",
author = "Raghu Mirmira and Tager, {Howard S.}",
year = "1991",
language = "English (US)",
volume = "30",
pages = "8222--8229",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "33",

}

TY - JOUR

T1 - Disposition of the phenylalanine B25 side chain during insulin-receptor and insulin-insulin interactions

AU - Mirmira, Raghu

AU - Tager, Howard S.

PY - 1991

Y1 - 1991

N2 - By the semisynthesis of both full-length insulin analogues and their des-pentapeptide-(B26-B30)-α-carboxamide counterparts, we have examined the importance of the electronic character and bulk of the position B25 side chain both in directing insulin interaction with its receptor on isolated canine hepatocytes and in determining the ability of insulin to self-associate in solution. Analogues include those in which PheB25 was replaced by cyclohexyl-Ala; Tyr; p-nitro-, p-fluoro- p-iodo- or p-amino-Phe; or p-amino-Phe in which the aromatic amino function had been acylated by the acetyl, hexanoyl, decanoyl, or 1-adamantanoyl group. Our findings identify that (a) the β-aromatic side chain at position B25 is indeed critical for high-affinity ligand-receptor interactions, (b) neither electron withdrawal from nor electron donation to the β-aromatic ring perturbs ligand-receptor interactions in major ways, (c) considerable lattitude is allowed the placement of linear or polycyclic apolar mass at the para position in p-amino-PheB25-substituted analogues with respect both to receptor binding affinity and to biological activity in vivo, and (d) para apolar mass at position B25 is readily accommodated during the self-association of insulin monomers, as assessed by analytical tyrosine radioiodination and spectroscopic analysis of analogue complexes with Co2+ and Co3+. These findings are discussed in terms of a model for insulin-receptor interactions at the cell membrane in which the position B25 side chain defines the edge of intermolecular contact.

AB - By the semisynthesis of both full-length insulin analogues and their des-pentapeptide-(B26-B30)-α-carboxamide counterparts, we have examined the importance of the electronic character and bulk of the position B25 side chain both in directing insulin interaction with its receptor on isolated canine hepatocytes and in determining the ability of insulin to self-associate in solution. Analogues include those in which PheB25 was replaced by cyclohexyl-Ala; Tyr; p-nitro-, p-fluoro- p-iodo- or p-amino-Phe; or p-amino-Phe in which the aromatic amino function had been acylated by the acetyl, hexanoyl, decanoyl, or 1-adamantanoyl group. Our findings identify that (a) the β-aromatic side chain at position B25 is indeed critical for high-affinity ligand-receptor interactions, (b) neither electron withdrawal from nor electron donation to the β-aromatic ring perturbs ligand-receptor interactions in major ways, (c) considerable lattitude is allowed the placement of linear or polycyclic apolar mass at the para position in p-amino-PheB25-substituted analogues with respect both to receptor binding affinity and to biological activity in vivo, and (d) para apolar mass at position B25 is readily accommodated during the self-association of insulin monomers, as assessed by analytical tyrosine radioiodination and spectroscopic analysis of analogue complexes with Co2+ and Co3+. These findings are discussed in terms of a model for insulin-receptor interactions at the cell membrane in which the position B25 side chain defines the edge of intermolecular contact.

UR - http://www.scopus.com/inward/record.url?scp=0026046559&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026046559&partnerID=8YFLogxK

M3 - Article

VL - 30

SP - 8222

EP - 8229

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 33

ER -