3bxq
From Proteopedia
The structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition
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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe zinc insulin hexamer undergoes allosteric reorganization among three conformational states, designated T(6), T(3)R(3)(f), and R(6). Although the free monomer in solution (the active species) resembles the classical T-state, an R-like conformational change is proposed to occur upon receptor binding. Here, we distinguish between the conformational requirements of receptor binding and the crystallographic TR transition by design of an active variant refractory to such reorganization. Our strategy exploits the contrasting environments of His(B5) in wild-type structures: on the T(6) surface but within an intersubunit crevice in R-containing hexamers. The TR transition is associated with a marked reduction in His(B5) pK(a), in turn predicting that a positive charge at this site would destabilize the R-specific crevice. Remarkably, substitution of His(B5) (conserved among eutherian mammals) by Arg (occasionally observed among other vertebrates) blocks the TR transition, as probed in solution by optical spectroscopy. Similarly, crystallization of Arg(B5)-insulin in the presence of phenol (ordinarily a potent inducer of the TR transition) yields T(6) hexamers rather than R(6) as obtained in control studies of wild-type insulin. The variant structure, determined at a resolution of 1.3A, closely resembles the wild-type T(6) hexamer. Whereas Arg(B5) is exposed on the protein surface, its side chain participates in a solvent-stabilized network of contacts similar to those involving His(B5) in wild-type T-states. The substantial receptor-binding activity of Arg(B5)-insulin (40% relative to wild type) demonstrates that the function of an insulin monomer can be uncoupled from its allosteric reorganization within zinc-stabilized hexamers. The structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition.,Wan ZL, Huang K, Hu SQ, Whittaker J, Weiss MA J Biol Chem. 2008 Jul 25;283(30):21198-210. Epub 2008 May 20. PMID:18492668[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Hu SQ | Huang K | Wan ZL | Weiss MA | Whittaker J
