5hpu

Insulin with proline analog HyP at position B28 in the R6 stateInsulin with proline analog HyP at position B28 in the R6 state

Structural highlights 5hpu is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , NonStd Res: Related: 5hpr Gene: INS (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 Daily injections of insulin provide lifesaving benefits to millions of diabetics. But currently available prandial insulins are suboptimal: The onset of action is delayed by slow dissociation of the insulin hexamer in the subcutaneous space, and insulin forms amyloid fibrils upon storage in solution. Here we show, through the use of noncanonical amino acid mutagenesis, that replacement of the proline residue at position 28 of the insulin B-chain (ProB28) by (4S)-hydroxyproline (Hzp) yields an active form of insulin that dissociates more rapidly, and fibrillates more slowly, than the wild-type protein. Crystal structures of dimeric and hexameric insulin preparations suggest that a hydrogen bond between the hydroxyl group of Hzp and a backbone amide carbonyl positioned across the dimer interface may be responsible for the altered behavior. The effects of hydroxylation are stereospecific; replacement of ProB28 by (4R)-hydroxyproline (Hyp) causes little change in the rates of fibrillation and hexamer disassociation. These results demonstrate a new approach that fuses the concepts of medicinal chemistry and protein design, and paves the way to further engineering of insulin and other therapeutic proteins. 4S-Hydroxylation of Insulin at ProB28 Accelerates Hexamer Dissociation and Delays Fibrillation.,Lieblich SA, Fang KY, Cahn JKB, Rawson J, LeBon J, Ku HT, Tirrell DA J Am Chem Soc. 2017 Jun 28;139(25):8384-8387. doi: 10.1021/jacs.7b00794. Epub, 2017 Jun 20. PMID:28598606 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 5hpu, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image