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Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues.

Jirácek J, Záková L, Antolíková E, Watson CJ, Turkenburg JP, Dodson GG, Brzozowski AM
Proc Natl Acad Sci U S A 107 1966-70 (2010)
Related entries: 2wru, 2wrv, 2wrw, 2wrx, 2ws0, 2ws1, 2ws4, 2ws6

Cited: 32 times
EuropePMC logo PMID: 20133841

Abstract

Insulin is a key protein hormone that regulates blood glucose levels and, thus, has widespread impact on lipid and protein metabolism. Insulin action is manifested through binding of its monomeric form to the Insulin Receptor (IR). At present, however, our knowledge about the structural behavior of insulin is based upon inactive, multimeric, and storage-like states. The active monomeric structure, when in complex with the receptor, must be different as the residues crucial for the interactions are buried within the multimeric forms. Although the exact nature of the insulin's induced-fit is unknown, there is strong evidence that the C-terminal part of the B-chain is a dynamic element in insulin activation and receptor binding. Here, we present the design and analysis of highly active (200-500%) insulin analogues that are truncated at residue 26 of the B-chain (B(26)). They show a structural convergence in the form of a new beta-turn at B(24)-B(26). We propose that the key element in insulin's transition, from an inactive to an active state, may be the formation of the beta-turn at B(24)-B(26) associated with a trans to cis isomerisation at the B(25)-B(26) peptide bond. Here, this turn is achieved with N-methylated L-amino acids adjacent to the trans to cis switch at the B(25)-B(26) peptide bond or by the insertion of certain D-amino acids at B(26). The resultant conformational changes unmask previously buried amino acids that are implicated in IR binding and provide structural details for new approaches in rational design of ligands effective in combating diabetes.

Articles - 2ws7 mentioned but not cited (1)

  1. Non-equivalent role of inter- and intramolecular hydrogen bonds in the insulin dimer interface. Antolíková E, Žáková L, Turkenburg JP, Watson CJ, Hančlová I, Šanda M, Cooper A, Kraus T, Brzozowski AM, Jiráček J. J Biol Chem 286 36968-36977 (2011)


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  12. Long-term glycemic control and prevention of diabetes complications in vivo using oleic acid-grafted-chitosan‑zinc-insulin complexes incorporated in thermosensitive copolymer. Sharma D, Singh J. J Control Release 323 161-178 (2020)
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  14. Mutations at hypothetical binding site 2 in insulin and insulin-like growth factors 1 and 2 result in receptor- and hormone-specific responses. Macháčková K, Mlčochová K, Potalitsyn P, Hanková K, Socha O, Buděšínský M, Muždalo A, Lepšík M, Černeková M, Radosavljević J, Fábry M, Mitrová K, Chrudinová M, Lin J, Yurenko Y, Hobza P, Selicharová I, Žáková L, Jiráček J. J Biol Chem 294 17371-17382 (2019)
  15. Structural and functional study of the GlnB22-insulin mutant responsible for maturity-onset diabetes of the young. Křížková K, Veverka V, Maletínská L, Hexnerová R, Brzozowski AM, Jiráček J, Žáková L. PLoS One 9 e112883 (2014)
  16. Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain. Hexnerová R, Křížková K, Fábry M, Sieglová I, Kedrová K, Collinsová M, Ullrichová P, Srb P, Williams C, Crump MP, Tošner Z, Jiráček J, Veverka V, Žáková L. J Biol Chem 291 21234-21245 (2016)
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  19. Insulin mimetic peptide S371 folds into a helical structure. Mohammadiarani H, Vashisth H. J Comput Chem 38 1158-1166 (2017)
  20. The efficiency of insulin production and its content in insulin-expressing model β-cells correlate with their Zn2+ levels. Dzianová P, Asai S, Chrudinová M, Kosinová L, Potalitsyn P, Šácha P, Hadravová R, Selicharová I, Kříž J, Turkenburg JP, Brzozowski AM, Jiráček J, Žáková L. Open Biol 10 200137 (2020)
  21. Elucidating the Activation Mechanism of the Insulin-Family Proteins with Molecular Dynamics Simulations. Papaioannou A, Kuyucak S, Kuncic Z. PLoS One 11 e0161459 (2016)
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  23. Computational study of the activity, dynamics, energetics and conformations of insulin analogues using molecular dynamics simulations: Application to hyperinsulinemia and the critical residue B26. Papaioannou A, Kuyucak S, Kuncic Z. Biochem Biophys Rep 11 182-190 (2017)
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  25. An Investigation into the Acidity-Induced Insulin Agglomeration: Implications for Drug Delivery and Translation. Fagihi MHA, Premathilaka C, O'Neill T, Garré M, Bhattacharjee S. ACS Omega 8 25279-25287 (2023)
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