ArticleThe Journal of biological chemistry2016
Contribution of TyrB26 to the Function and Stability of Insulin: STRUCTURE-ACTIVITY RELATIONSHIPS AT A CONSERVED HORMONE-RECEPTOR INTERFACE.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Synthesis of a highly thermostable insulin by phenylalanine conjugation at B29 Lysine.Communications chemistry · 2024Article
- Mechanistic Insights Behind the Self-Assembly of Human Insulin under the Influence of Surface-Engineered Gold Nanoparticles.ACS chemical neuroscience · 2024Article
- Structural basis of insulin fibrillation.Science advances · 2023Article
- Understanding Insulin in the Age of Precision Medicine and Big Data: Under-Explored Nature of Genomics.Biomolecules · 2023Review
- Article
- Single-chain insulin analogs threaded by the insulin receptor αCT domain.Biophysical journal · 2022Article
- Phenolic Preservative Removal from Commercial Insulin Formulations Reduces Tissue Inflammation while Maintaining Euglycemia.ACS pharmacology & translational science · 2021Article
- Structural Lessons From the Mutant Proinsulin Syndrome.Frontiers in endocrinology · 2021Review
- Evolution of insulin at the edge of foldability and its medical implications.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Role of Proinsulin Self-Association in MutantDiabetes · 2020Article
- "Register-shift" insulin analogs uncover constraints of proteotoxicity in protein evolution.The Journal of biological chemistry · 2020Article
- Substitution of an Internal Disulfide Bridge with a Diselenide Enhances both Foldability and Stability of Human Insulin.Chemistry (Weinheim an der Bergstrasse, Germany) · 2019Article
- A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding.The Journal of biological chemistry · 2018Article
- Biosynthesis, structure, and folding of the insulin precursor protein.Diabetes, obesity & metabolism · 2018Review
- A thing of beauty: Structure and function of insulin's "aromatic triplet".Diabetes, obesity & metabolism · 2018Review
- Structure-based stabilization of insulin as a therapeutic protein assembly via enhanced aromatic-aromatic interactions.The Journal of biological chemistry · 2018Article
- An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein.The Journal of biological chemistry · 2018Article
- Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding.The Journal of biological chemistry · 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
- Scope and Limitations of Fmoc Chemistry SPPS-Based Approaches to the Total Synthesis of Insulin Lispro via Ester Insulin.Chemistry (Weinheim an der Bergstrasse, Germany) · 2017Article
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6 authors.
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Abstract
Crystallographic studies of insulin bound to receptor domains have defined the primary hormone-receptor interface. We investigated the role of Tyr(B26), a conserved aromatic residue at this interface. To probe the evolutionary basis for such conservation, we constructed 18 variants at B26. Surprisingly, non-aromatic polar or charged side chains (such as Glu, Ser, or ornithine (Orn)) conferred high activity, whereas the weakest-binding analogs contained Val, Ile, and Leu substitutions. Modeling of variant complexes suggested that the B26 side chains pack within a shallow depression at the solvent-exposed periphery of the interface. This interface would disfavor large aliphatic side chains. The analogs with highest activity exhibited reduced thermodynamic stability and heightened susceptibility to fibrillation. Perturbed self-assembly was also demonstrated in studies of the charged variants (Orn and Glu); indeed, the Glu(B26) analog exhibited aberrant aggregation in either the presence or absence of zinc ions. Thus, although Tyr(B26) is part of insulin's receptor-binding surface, our results suggest that its conservation has been enjoined by the aromatic ring's contributions to native stability and self-assembly. We envisage that such classical structural relationships reflect the implicit threat of toxic misfolding (rather than hormonal function at the receptor level) as a general evolutionary determinant of extant protein sequences.
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