2wc0

crystal structure of human insulin degrading enzyme in complex with iodinated insulin

spinqualitylabelsall models 2wc0, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2wc0 is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DIO, ZN Related: 1hit, 2jbu, 2hho, 2c8q, 1tyl, 2c8r, 1t1k, 1aiy, 1xda, 1htv, 1mso, 1uz9, 1fub, 1tym, 1hui, 1vkt, 2vk0, 1t1q, 2ceu, 1hls, 1qj0, 1fu2, 1mhj, 1sjt, 1qiy, 1iog, 2vjz, 1ioh, 1trz, 1evr, 1ev3, 1rwe, 1os4, 1guj, 1ai0, 1jco, 1sf1, 1jca, 1zeg, 1os3, 1xgl, 1qiz, 1t0c, 1g7b, 2wby, 2aiy, 1ev6, 1q4v, 2hh4, 2h67, 4aiy, 1j73, 1k3m, 1mhi, 2hiu, 1kmf, 1xw7, 5aiy, 1g7a, 1znj, 1zeh, 1his, 1b9e, 1w8p, 3aiy, 1hiq, 1lph, 1efe, 1a7f, 1t1p, 1ben, 1lkq, 2jg4 Activity: Insulysin, with EC number 3.4.24.56 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. 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 PubMed Insulin is a hormone vital for glucose homeostasis, and insulin-degrading enzyme (IDE) plays a key role in its clearance. IDE exhibits a remarkable specificity to degrade insulin without breaking the disulfide bonds that hold the insulin A and B chains together. Using Fourier transform ion cyclotron resonance (FTICR) mass spectrometry to obtain high mass accuracy, and electron capture dissociation (ECD) to selectively break the disulfide bonds in gas phase fragmentation, we determined the cleavage sites and composition of human insulin fragments generated by human IDE. Our time-dependent analysis of IDE-digested insulin fragments reveals that IDE is highly processive in its initial cleavage at the middle of both the insulin A and B chains. This ensures that IDE effectively splits insulin into inactive N- and C-terminal halves without breaking the disulfide bonds. To understand the molecular basis of the recognition and unfolding of insulin by IDE, we determined a 2.6-A resolution insulin-bound IDE structure. Our structure reveals that IDE forms an enclosed catalytic chamber that completely engulfs and intimately interacts with a partially unfolded insulin molecule. This structure also highlights how the unique size, shape, charge distribution, and exosite of the IDE catalytic chamber contribute to its high affinity ( approximately 100 nm) for insulin. In addition, this structure shows how IDE utilizes the interaction of its exosite with the N terminus of the insulin A chain as well as other properties of the catalytic chamber to guide the unfolding of insulin and allowing for the processive cleavages. Molecular basis of catalytic chamber-assisted unfolding and cleavage of human insulin by human insulin-degrading enzyme.,Manolopoulou M, Guo Q, Malito E, Schilling AB, Tang WJ J Biol Chem. 2009 May 22;284(21):14177-88. Epub 2009 Mar 25. PMID:19321446 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Insulin 3D Structures Insulin-degrading enzyme 3D structures

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