7sth | pdb_00007sth

Full-length insulin receptor bound with unsaturated insulin WT (2 insulin bound) symmetric conformation

spinqualitylabelsall models 7sth, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7sth is a 4 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.5Å 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 Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. IR with one insulin bound adopts a Gamma-shaped conformation. IR with two insulins bound assumes a T-shaped conformation. One insulin binds at site-1 and another simultaneously contacts both site-1 and site-2 in the T-shaped IR dimer. We further show that concurrent binding of four insulins to sites-1 and -2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation. Synergistic activation of the insulin receptor via two distinct sites.,Li J, Park J, Mayer JP, Webb KJ, Uchikawa E, Wu J, Liu S, Zhang X, Stowell MHB, Choi E, Bai XC Nat Struct Mol Biol. 2022 Apr;29(4):357-368. doi: 10.1038/s41594-022-00750-6. , Epub 2022 Mar 31. PMID:35361965 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Insulin 3D Structures Insulin receptor 3D structures

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