2wru | pdb_00002wru

Semi-synthetic highly active analogue of human insulin NMeAlaB26-DTI- NH2

spinqualitylabelsall models 2wru, resolution 1.57Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2wru is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT NonStd Res: ZZJ Related: 1hit, 2hho, 2c8q, 1tyl, 2c8r, 1t1k, 1aiy, 1xda, 1htv, 1mso, 1uz9, 1fub, 1tym, 1hui, 2vk0, 1vkt, 1t1q, 1hls, 2ceu, 1qj0, 1mhj, 1fu2, 1sjt, 1qiy, 1iog, 2vjz, 1ioh, 1trz, 1evr, 1ev3, 1rwe, 1os4, 1guj, 1ai0, 1sf1, 1jco, 1jca, 1zeg, 1os3, 1xgl, 1t0c, 1qiz, 1g7b, 2wby, 2aiy, 1ev6, 1q4v, 2hh4, 2h67, 4aiy, 1j73, 1k3m, 1mhi, 2wc0, 2hiu, 1kmf, 1xw7, 5aiy, 1g7a, 1znj, 1zeh, 1his, 1b9e, 3aiy, 1w8p, 1hiq, 1lph, 1efe, 1a7f, 1t1p, 1ben, 1lkq, 2ws7, 2ws0, 2ws4, 2ws1, 2ws6, 2wrx, 2wrw, 2wrv 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 Insulin is a key protein hormone that regulates blood glucose levels and, thus, has widespread impact on lipid and protein metabolism. Insulin action is manifested through binding of its monomeric form to the Insulin Receptor (IR). At present, however, our knowledge about the structural behavior of insulin is based upon inactive, multimeric, and storage-like states. The active monomeric structure, when in complex with the receptor, must be different as the residues crucial for the interactions are buried within the multimeric forms. Although the exact nature of the insulin's induced-fit is unknown, there is strong evidence that the C-terminal part of the B-chain is a dynamic element in insulin activation and receptor binding. Here, we present the design and analysis of highly active (200-500%) insulin analogues that are truncated at residue 26 of the B-chain (B(26)). They show a structural convergence in the form of a new beta-turn at B(24)-B(26). We propose that the key element in insulin's transition, from an inactive to an active state, may be the formation of the beta-turn at B(24)-B(26) associated with a trans to cis isomerisation at the B(25)-B(26) peptide bond. Here, this turn is achieved with N-methylated L-amino acids adjacent to the trans to cis switch at the B(25)-B(26) peptide bond or by the insertion of certain D-amino acids at B(26). The resultant conformational changes unmask previously buried amino acids that are implicated in IR binding and provide structural details for new approaches in rational design of ligands effective in combating diabetes. Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues.,Jiracek J, Zakova L, Antolikova E, Watson CJ, Turkenburg JP, Dodson GG, Brzozowski AM Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1966-70. Epub 2010 Jan 25. PMID:20133841 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Molecular Playground/Insulin

Proteopedia Page Contributors and Editors (what is this?)

OCA