| Design of an insulin analog with enhanced receptor binding selectivity: rationale, structure, and therapeutic implications. | |
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MedLine Citation:
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PMID: 19773552 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Insulin binds with high affinity to the insulin receptor (IR) and with low affinity to the type 1 insulin-like growth factor (IGF) receptor (IGFR). Such cross-binding, which reflects homologies within the insulin-IGF signaling system, is of clinical interest in relation to the association between hyperinsulinemia and colorectal cancer. Here, we employ nonstandard mutagenesis to design an insulin analog with enhanced affinity for the IR but reduced affinity for the IGFR. Unnatural amino acids were introduced by chemical synthesis at the N- and C-capping positions of a recognition alpha-helix (residues A1 and A8). These sites adjoin the hormone-receptor interface as indicated by photocross-linking studies. Specificity is enhanced more than 3-fold on the following: (i) substitution of Gly(A1) by D-Ala or D-Leu, and (ii) substitution of Thr(A8) by diaminobutyric acid (Dab). The crystal structure of [D-Ala(A1),Dab(A8)]insulin, as determined within a T(6) zinc hexamer to a resolution of 1.35 A, is essentially identical to that of human insulin. The nonstandard side chains project into solvent at the edge of a conserved receptor-binding surface shared by insulin and IGF-I. Our results demonstrate that modifications at this edge discriminate between IR and IGFR. Because hyperinsulinemia is typically characterized by a 3-fold increase in integrated postprandial insulin concentrations, we envisage that such insulin analogs may facilitate studies of the initiation and progression of cancer in animal models. Future development of clinical analogs lacking significant IGFR cross-binding may enhance the safety of insulin replacement therapy in patients with type 2 diabetes mellitus at increased risk of colorectal cancer. |
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Authors:
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Ming Zhao; Zhu-li Wan; Linda Whittaker; Bin Xu; Nelson B Phillips; Panayotis G Katsoyannis; Faramarz Ismail-Beigi; Jonathan Whittaker; Michael A Weiss |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-09-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-11-09 Completed Date: 2009-12-24 Revised Date: 2012-04-05 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 32178-87 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/3FQ7 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Binding Sites Circular Dichroism Cross-Linking Reagents / pharmacology Crystallography, X-Ray Drug Design* Humans Insulin / analogs & derivatives*, chemistry, metabolism* Insulin-Like Growth Factor I / pharmacology Models, Chemical Models, Molecular Mutation / genetics Protein Folding Protein Structure, Tertiary Receptor, IGF Type 1 / genetics, metabolism* Receptor, Insulin / chemistry, genetics, metabolism* Structure-Activity Relationship |
| Grant Support | |
ID/Acronym/Agency:
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DK065890/DK/NIDDK NIH HHS; DK074176/DK/NIDDK NIH HHS; DK40949/DK/NIDDK NIH HHS; R01 DK040949-11/DK/NIDDK NIH HHS; R01 DK074176-01/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cross-Linking Reagents; 0/Insulin; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.10.1/Receptor, IGF Type 1; EC 2.7.10.1/Receptor, Insulin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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