CRYSTALLOGRAPHIC EVIDENCE FOR DUAL COORDINATION AROUND ZINC IN THE T3R3 HUMAN INSULIN HEXAMER
[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.  
[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 T3R3 human insulin hexamer (T and R referring to extended and alpha-helical conformations, respectively, of the first eight residues of the B-chain), complexed to two zinc ions, crystallizes in space group R3 with hexagonal cell constants a = 80.64 and c = 37.78 A. The structure has been refined to a residual of 0.172 using 9225 independent data to 1.6-A resolution. The asymmetric unit consists of a TR dimer, and the insulin hexamer is generated by the action of the crystallographic 3-fold axis. The conformation of one insulin trimer is nearly identical to that of the T6 hexamer, while the other trimer approximates that of the R6 hexamer, except for the three N-terminal B-chain residues that adopt an extended rather than an alpha-helical conformation. Each of the two zinc ions, which lie on the crystallographic 3-fold axis and exhibit two different, disordered coordination geometries, is coordinated by the imidazole groups of three symmetry-related B10 histidine residues. The coordination sphere of the zinc in the T3 trimer is either tetrahedral, with the fourth site filled by a chloride ion, or octahedral, completed by three water molecules. The coordination of the zinc in the 12-A narrow channel in the R3 trimer is tetrahedral, with either a second chloride ion or a water molecule completing the coordination sphere. The putative off-axial zinc binding sites that result from the T-->R transition of monomer II do not contain zinc ion, but instead are filled with clusters of ordered water molecules.(ABSTRACT TRUNCATED AT 250 WORDS)
Crystallographic evidence for dual coordination around zinc in the T3R3 human insulin hexamer.,Ciszak E, Smith GD Biochemistry. 1994 Feb 15;33(6):1512-7. PMID:8312271
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.