Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities

The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.

Download Full-text

Characterization of the Insulin Receptor by Using Photoreactive Insulin Analogues

Clinical Science ◽

10.1042/cs056020pa ◽

1979 ◽

Vol 56 (3) ◽

pp. 20P-20P

Author(s):

M. H. Wisher ◽

L. V. Campbell ◽

A. Khalili-Shirazi ◽

P. Thamm ◽

S. D. Brandenberg

Keyword(s):

Insulin Receptor ◽

Insulin Analogues

Download Full-text

Effect of thyroid hormone binding proteins on insulin receptor binding of B1-thyronine-insulin analogues

Biochemical Journal ◽

10.1042/bj20040177 ◽

2004 ◽

Vol 381 (1) ◽

pp. 51-57 ◽

Cited By ~ 3

Author(s):

Fariba SHOJAEE-MORADIE ◽

Michelle P. Y. CHAN ◽

Micayla A. TELFER ◽

Dietrich BRANDENBURG ◽

Erik SUNDERMANN ◽

...

Keyword(s):

Thyroid Hormone ◽

Insulin Receptor ◽

Receptor Binding ◽

Plasma Proteins ◽

Binding Proteins ◽

Insulin Analogues ◽

Free Form ◽

Hormone Binding ◽

Insulin Receptor Binding

Certain thyronine-insulin analogues, which form non-covalent complexes with plasma proteins, have been shown to act preferentially in the liver. We hypothesized that this property may be dependant on the ability of the analogue to bind to the insulin receptor without prior dissociation from the binding protein. NαB1-L-thyroxyl-insulin, NαB1-3,3′,5′-triiodothyronine-insulin, NαB1-D-thyroxyl-insulin and NαB1-L-thyroxyl-aminolauroyl-insulin were compared with insulin for their capacity to inhibit the binding of [125I]TyrA14-insulin to rat liver plasma membrane in albumin-free buffer. Effective doses at 50% maximum inhibition of binding (ED50) were calculated with and without addition of the thyroid hormone binding proteins transthyretin, thyroxine binding globulin and human serum albumin. The binding of thyronine-insulin analogues to insulin receptors was inhibited in a dose-dependant manner by the addition of thyroid hormone binding proteins at concentrations in the physiological range. Complexes of thyronine-insulin analogues with thyroid hormone binding proteins exhibit impaired insulin receptor binding affinities compared with those of the analogues in their free form. Hepatoselectivity in vivo may not depend on binding of the intact complexes to hepatocytes. These results have implications for the physiological role of hormone binding proteins and the in vivo properties of other insulin analogues which bind to plasma proteins.

Download Full-text

Engineering of Insulin Receptor Isoform-Selective Insulin Analogues

PLoS ONE ◽

10.1371/journal.pone.0020288 ◽

2011 ◽

Vol 6 (5) ◽

pp. e20288 ◽

Cited By ~ 13

Author(s):

Tine Glendorf ◽

Carsten E. Stidsen ◽

Mathias Norrman ◽

Erica Nishimura ◽

Anders R. Sørensen ◽

...

Keyword(s):

Insulin Receptor ◽

Insulin Analogues

Download Full-text

Use of high affinity insulin analogues to assess the functional relationships between insulin receptor trafficking, mitogenic signaling and mRNA expression in rat liver

Biochimie ◽

10.1016/j.biochi.2004.03.005 ◽

2004 ◽

Vol 86 (3) ◽

pp. 157-166 ◽

Cited By ~ 6

Author(s):

François Authier ◽

Clémence Merlen ◽

Mohamed Amessou ◽

Gillian M. Danielsen

Keyword(s):

Insulin Receptor ◽

Mrna Expression ◽

Rat Liver ◽

Insulin Analogues ◽

Receptor Trafficking ◽

Mitogenic Signaling ◽

Functional Relationships ◽

High Affinity

Download Full-text

Introduction of mutations in insulin molecule: positive and negative mutations

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20146004430 ◽

2014 ◽

Vol 60 (4) ◽

pp. 430-437

Author(s):

O.I. Ksenofontova

Keyword(s):

Diabetes Mellitus ◽

Drug Development ◽

Insulin Receptor ◽

Insulin Analogues ◽

Receptor Interaction ◽

Insulin Superfamily ◽

Insulin Molecule ◽

Treatment Of Diabetes ◽

Neutral Mutations

Introduction of mutations in an insulin molecule is one of the important approaches to drug development for treatment of diabetes mellitus. Generally, usage of mutations is aimed at activation of insulin and insulin receptor interaction. Such mutations can be considered as positive. Mutations that reduce the binding efficacy are negative. There are neutral mutations as well. This article considers both natural mutations that are typical for various members of the insulin superfamily and artificial ones which are introduced to improve the insulin pharmacological characteristics. Data presented here can be useful in developing new effective insulin analogues for treatment of diabetes mellitus.

Download Full-text

Alternative signaling network activation through different insulin receptor family members caused by pro-mitogenic antidiabetic insulin analogues in human mammary epithelial cells

Breast Cancer Research ◽

10.1186/s13058-015-0600-5 ◽

2015 ◽

Vol 17 (1) ◽

Cited By ~ 6

Author(s):

Bas ter Braak ◽

Steven Wink ◽

Esmee Koedoot ◽

Chantal Pont ◽

Christine Siezen ◽

...

Keyword(s):

Epithelial Cells ◽

Insulin Receptor ◽

Mammary Epithelial Cells ◽

Insulin Analogues ◽

Signaling Network ◽

Mammary Epithelial ◽

Human Mammary Epithelial Cells ◽

Network Activation ◽

Human Mammary Epithelial ◽

Receptor Family

Download Full-text

Timing-dependence of insulin-receptor mitogenic versus metabolic signalling: a plausible model based on coincidence of hormone and effector binding

Biochemical Journal ◽

10.1042/bj3390675 ◽

1999 ◽

Vol 339 (3) ◽

pp. 675-683 ◽

Cited By ~ 12

Author(s):

Ronald M. SHYMKO ◽

Erik DUMONT ◽

Pierre DE MEYTS ◽

Jacques E. DUMONT

Keyword(s):

Insulin Receptor ◽

Insulin Analogues ◽

Dissociation Rate ◽

Binding Kinetics ◽

Hormone Binding ◽

Dissociation Kinetics ◽

Metabolic Signalling ◽

Mitogenic Signalling ◽

Single Effector ◽

Effector Binding

Mitogenic signalling through the insulin receptor is enhanced compared with metabolic signalling for insulin analogues having slower dissociation kinetics than insulin itself. A plausible explanation in molecular terms of this timing-dependent specificity is lacking. We show here that if signalling is transmitted through a single effector, binding coincidentally with hormone to the insulin receptor and whose association and dissociation kinetics are slow relative to the hormone dissociation rate, the resulting biological effect is predicted to be dependent on hormone-binding kinetics. However, known primary effector molecules associating with the insulin receptor bind and interact rapidly with the receptor, contrary to the assumptions of the single-effector model. A model with two effectors which must bind coincidentally with hormone for signalling to occur also gives the required dependence of signalling on hormone-binding kinetics, provided that at least one of the effectors has slow binding kinetics relative to hormone binding. In this case, the other effector can have rapid kinetics, which is consistent with the properties of the major known substrates of the insulin receptor, such as the insulin receptor substrate (IRS) molecules.

Download Full-text