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INSULIN MUTANT A8 HIS,(B1, B10, B16, B27)GLU, DES-B30, NMR, 26 STRUCTURESINSULIN MUTANT A8 HIS,(B1, B10, B16, B27)GLU, DES-B30, NMR, 26 STRUCTURES
Structural highlights
DiseaseINS_HUMAN Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:176730.[1] [2] [3] [4] Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:125852. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.[5] Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:606176. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.[6] [7] Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:613370. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.[8] [9] [10] FunctionINS_HUMAN Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver. Publication Abstract from PubMedStudies of naturally occuring and chemically modified insulins have established that the NH2-terminal helix of the A-chain is important in conferring affinity in insulin-receptor interactions. Nevertheless, the three-dimensional structural basis for these observations has not previously been studied in detail. To correlate structure and function in this region of the molecule, we have used the solution structure of an engineered monomer (GluB1, GluB10, GluB16, GluB27, desB30)-insulin (4E insulin) as a template for design of A-chain mutants associated with enhanced or greatly diminished affinity for the insulin receptor. In the context of 4E insulin, the employed mutants, i.e. ThrA8-->His and ValA3-->Gly, result in species with 143% and 0.1% biological activity, respectively, relative to human insulin. The high-resolution NMR studies reveal two well-defined structures each resembling the template. However, significant structural differences are evident notably in residues A2-A8 and their immediate environment. In comparison with the template structure, the A8His mutation enhances the helical character of residues A2-A8. This structural change leads to additional exposure of a hydrophobic patch mainly consisting of species invariant residues. In contrast, the A3Gly mutation leads to stretching and disruption of the A2-A8 helix and changes both the dimensions and the access to the hydrophobic patch exposed in the more active insulins. We conclude that the mutations induce small, yet decisive structural changes that either mediate or inhibit the subtle conformational adjustments involved in the presentation of this part of the insulin pharmacophore to the receptor. The relationship between insulin bioactivity and structure in the NH2-terminal A-chain helix.,Olsen HB, Ludvigsen S, Kaarsholm NC J Mol Biol. 1998 Nov 27;284(2):477-88. PMID:9813131[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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