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From Proteopedia
HUMAN INSULIN HEXAMERS WITH CHAIN B HIS MUTATED TO TYR COMPLEXED WITH RESORCINOL
Structural highlights
Disease[INS_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] 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. 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 addition of phenols to hexameric insulin solutions produces a particularly stable hexamer, resulting from a rearrangement in which residues B1-B8 change from an extended conformation (T-state) to form an alpha-helix (R-state). The R-state is, in part, stabilized by nonpolar interactions between the phenolic molecule and residue B5 His at the dimer-dimer interface. The B5 His --> Tyr mutant human insulin was constructed to see if the tyrosine side chain would mimic the effect of phenol binding in the hexamer and induce the R-state. In partial support of this hypothesis, the molecule crystallized as a half-helical hexamer (T(3)R(3)) in conditions that conventionally promote the fully nonhelical (T6) form. As expected, in the presence of phenol or resorcinol, the B5 Tyr hexamers adopt the fully helical (R6) conformation. Molecular modeling calculations were performed to investigate the conformational preference of the T-state B5 Tyr side chain in the T(3)R(3) form, this side chain being associated with structural perturbations of the A7-A10 loop in an adjacent hexamer. For an isolated dimer, several different orientations of the side chain were found, which were close in energy and readily interconvertible. In the crystal environment only one of these conformations remains low in energy; this conformation corresponds to that observed in the crystal structure. This suggests that packing constraints around residue B5 Tyr result in the observed structural rearrangements. Thus, rather than promoting the R-state in a manner analogous to phenol, the mutation appears to destabilize the T-state. These studies highlight the role of B5 His in determining hexamer conformation and in mediating crystal packing interactions, properties that are likely be important in vivo. Structural consequences of the B5 histidine --> tyrosine mutation in human insulin characterized by X-ray crystallography and conformational analysis.,Tang L, Whittingham JL, Verma CS, Caves LS, Dodson GG Biochemistry. 1999 Sep 14;38(37):12041-51. PMID:10508408[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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