2mvc

Solution structure of human insulin at pH 1.9

spinqualitylabelsall models 2mvc, 50 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2mvc is a 2 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 2hiu, 2mvd Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum Disease [INS_HUMAN] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:176730]. 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. 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. 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. Function [INS_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 PubMed The insulin gene mutation c.137G>A (R46Q), which changes an arginine at the B22 position of the mature hormone to glutamine, causes the monogenic diabetes variant maturity-onset diabetes of the young (MODY). In MODY patients, this mutation is heterozygous, and both mutant and wild-type (WT) human insulin are produced simultaneously. However, the patients often depend on administration of exogenous insulin. In this study, we chemically synthesized the MODY mutant [GlnB22]-insulin and characterized its biological and structural properties. The chemical synthesis of this insulin analogue revealed that its folding ability is severely impaired. In vitro and in vivo tests showed that its binding affinity and biological activity are reduced (both approximately 20% that of human insulin). Comparison of the solution structure of [GlnB22]-insulin with the solution structure of native human insulin revealed that the most significant structural effect of the mutation is distortion of the B20-B23 beta-turn, leading to liberation of the B chain C-terminus from the protein core. The distortion of the B20-B23 beta-turn is caused by the extended conformational freedom of the GlnB22 side chain, which is no longer anchored in a hydrogen bonding network like the native ArgB22. The partially disordered [GlnB22]-insulin structure appears to be one reason for the reduced binding potency of this mutant and may also be responsible for its low folding efficiency in vivo. The altered orientation and flexibility of the B20-B23 beta-turn may interfere with the formation of disulfide bonds in proinsulin bearing the R46Q (GlnB22) mutation. This may also have a negative effect on the WT proinsulin simultaneously biosynthesized in beta-cells and therefore play a major role in the development of MODY in patients producing [GlnB22]-insulin. Structural and Functional Study of the GlnB22-Insulin Mutant Responsible for Maturity-Onset Diabetes of the Young.,Krizkova K, Veverka V, Maletinska L, Hexnerova R, Brzozowski AM, Jiracek J, Zakova L PLoS One. 2014 Nov 25;9(11):e112883. doi: 10.1371/journal.pone.0112883., eCollection 2014. PMID:25423173 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Molecular Playground/Insulin

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