A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00498264" target="_blank" >RIV/61388963:_____/18:00498264 - isvavai.cz</a>
Result on the web
<a href="http://www.jbc.org/content/293/43/16818.full" target="_blank" >http://www.jbc.org/content/293/43/16818.full</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1074/jbc.RA118.004852" target="_blank" >10.1074/jbc.RA118.004852</a>
Alternative languages
Result language
angličtina
Original language name
A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding
Original language description
Insulin and insulin-like growth factor 1 (IGF-1) are closely related hormones involved in the regulation of metabolism and growth. They elicit their functions through activation of tyrosine kinase-type receptors: insulin receptors (IR-A and IR-B) and IGF-1 receptor (IGF-1R). Despite similarity in primary and three-dimensional structures, insulin and IGF-1 bind the noncognate receptor with substantially reduced affinity. We prepared [d-His(B24), Gly(B31), Tyr(B32)]-insulin, which binds all three receptors with high affinity (251 or 338% binding affinity to IR-A respectively to IR-B relative to insulin and 12.4% binding affinity to IGF-1R relative to IGF-1). We prepared other modified insulins with the aim of explaining the versatility of [d-His(B24), Gly(B31), Tyr(B32)]-insulin. Through structural, activity, and kinetic studies of these insulin analogs, we concluded that the ability of [d-His(B24), Gly(B31), Tyr(B32)]-insulin to stimulate all three receptors is provided by structural changes caused by a reversed chirality at the B24 combined with the extension of the C terminus of the B chain by two extra residues. We assume that the structural changes allow the directing of the B chain C terminus to some extra interactions with the receptors. These unusual interactions lead to a decrease of dissociation rate from the IR and conversely enable easier association with IGF-1R. All of the structural changes were made at the hormones' Site 1, which is thought to interact with the Site 1 of the receptors. The results of the study suggest that merely modifications of Site 1 of the hormone are sufficient to change the receptor specificity of insulin.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/EF16_019%2F0000729" target="_blank" >EF16_019/0000729: Chemical biology for drugging undruggable targets</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Biological Chemistry
ISSN
0021-9258
e-ISSN
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Volume of the periodical
293
Issue of the periodical within the volume
43
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
16818-16829
UT code for WoS article
000448515100022
EID of the result in the Scopus database
2-s2.0-85055616917