ArticleBiochemistry2014
Insight into the structural and biological relevance of the T/R transition of the N-terminus of the B-chain in human insulin.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 37 citations in OpenAlex.
- An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling.Science advances · 2026Article
- Exploring proinsulin proteostasis: insights into beta cell health and diabetes.Frontiers in molecular biosciences · 2025Review
- A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression.Molecular metabolism · 2024Article
- The TActa crystallographica. Section D, Structural biology · 2023Article
- Characterization of insulin crystalline form in isolated β-cell secretory granules.Open biology · 2022Article
- Unraveling the Impact of pH on the Crystallization of Pharmaceutical Proteins: A Case Study of Human Insulin.Crystal growth & design · 2022Article
- The Possible Role of the Type I Chaperonins in Human Insulin Self-Association.Life (Basel, Switzerland) · 2022Article
- Progress in Simulation Studies of Insulin Structure and Function.Frontiers in endocrinology · 2022Review
- Computational IR Spectroscopy of Insulin Dimer Structure and Conformational Heterogeneity.The journal of physical chemistry. B · 2021Article
- Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques.Scientific reports · 2021Article
- The efficiency of insulin production and its content in insulin-expressing model β-cells correlate with their ZnOpen biology · 2020Article
- Article
- Mutations at hypothetical binding site 2 in insulin and insulin-like growth factors 1 and 2 result in receptor- and hormone-specific responses.The Journal of biological chemistry · 2019Article
- Evidence of oligomerization of bovine insulin in solution given by NMR.European biophysics journal : EBJ · 2018Article
- Computational study of the activity, dynamics, energetics and conformations of insulin analogues using molecular dynamics simulations: Application to hyperinsulinemia and the critical residue B26.Biochemistry and biophysics reports · 2017Article
- Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain.The Journal of biological chemistry · 2016Article
- Rational steering of insulin binding specificity by intra-chain chemical crosslinking.Scientific reports · 2016Article
- Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding.PloS one · 2015Article
- Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex.Acta crystallographica. Section D, Biological crystallography · 2014Article
- Structural and functional study of the GlnB22-insulin mutant responsible for maturity-onset diabetes of the young.PloS one · 2014Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
The N-terminus of the B-chain of insulin may adopt two alternative conformations designated as the T- and R-states. Despite the recent structural insight into insulin-insulin receptor (IR) complexes, the physiological relevance of the T/R transition is still unclear. Hence, this study focused on the rational design, synthesis, and characterization of human insulin analogues structurally locked in expected R- or T-states. Sites B3, B5, and B8, capable of affecting the conformation of the N-terminus of the B-chain, were subjects of rational substitutions with amino acids with specific allowed and disallowed dihedral φ and ψ main-chain angles. α-Aminoisobutyric acid was systematically incorporated into positions B3, B5, and B8 for stabilization of the R-state, and N-methylalanine and d-proline amino acids were introduced at position B8 for stabilization of the T-state. IR affinities of the analogues were compared and correlated with their T/R transition ability and analyzed against their crystal and nuclear magnetic resonance structures. Our data revealed that (i) the T-like state is indeed important for the folding efficiency of (pro)insulin, (ii) the R-state is most probably incompatible with an active form of insulin, (iii) the R-state cannot be induced or stabilized by a single substitution at a specific site, and (iv) the B1-B8 segment is capable of folding into a variety of low-affinity T-like states. Therefore, we conclude that the active conformation of the N-terminus of the B-chain must be different from the "classical" T-state and that a substantial flexibility of the B1-B8 segment, where GlyB8 plays a key role, is a crucial prerequisite for an efficient insulin-IR interaction.
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