4p65

Crystal structure of an cyclohexylalanine substituted insulin analog.

spinqualitylabelsall models 4p65, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4p65 is a 12 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, IPH, ZN NonStd Res: ALC, ORN Resources: FirstGlance, OCA, 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 Crystallographic studies of insulin bound to fragments of the insulin receptor have recently defined the topography of the primary hormone-receptor interface. Here, we have investigated the role of PheB24, an invariant aromatic anchor at this interface and site of a human mutation causing diabetes mellitus. An extensive set of B24 substitutions has been constructed and tested for effects on receptor binding. Although aromaticity has long been considered a key requirement at this position, MetB24 was found to confer essentially native affinity and bioactivity. Molecular modeling suggests that this linear side chain can serve as an alternative hydrophobic anchor at the hormone-receptor interface. These findings motivated further substitution of PheB24 by cyclohexanylalanine (Cha), which contains a non-planar aliphatic ring. Contrary to expectations, ChaB24-insulin likewise exhibited high activity. Further, its resistance to fibrillation and rapid rate of hexamer disassembly-properties of potential therapeutic advantage-were enhanced. The crystal structure of the ChaB24 analog, determined as an R6 zinc-stabilized hexamer at a resolution of 1.5 A, closely resembles that of wild-type insulin. The non-planar aliphatic ring exhibits two chair conformations with partial occupancies, each recapitulating the role of PheB24 at the dimer interface. Together, these studies have defined structural requirements of an anchor residue within the B24-binding pocket of the insulin receptor; similar molecular principles are likely to pertain to insulin-related growth factors. Our results highlight in particular the utility of non-aromatic side chains as probes of the B24 pocket and suggest that the non-standard Cha side chain may have therapeutic utility. Aromatic Anchor at an Invariant Hormone-Receptor Interface. FUNCTION OF INSULIN RESIDUE B24 WITH APPLICATION TO PROTEIN DESIGN.,Pandyarajan V, Smith BJ, Phillips NB, Whittaker L, Cox GP, Wickramasinghe N, Menting JG, Wan ZL, Whittaker J, Ismail-Beigi F, Lawrence MC, Weiss MA J Biol Chem. 2014 Oct 10. pii: jbc.M114.608562. PMID:25305014 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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