6h1a

Crystal structure of VX surrogate NEMP inhibited recombinant human bile salt activated lipase

spinqualitylabelsall models 6h1a, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6h1a is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: ACT, SVX, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CEL_HUMAN Defects in CEL are a cause of maturity-onset diabetes of the young type 8 with exocrine dysfunction (MODY8) [MIM:609812; also known as diabetes and pancreatic exocrine dysfunction (DPED). MODY 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 CEL_HUMAN Catalyzes fat and vitamin absorption. Acts in concert with pancreatic lipase and colipase for the complete digestion of dietary triglycerides. Publication Abstract from PubMed The efficiency of human butyrylcholinesterase (BChE) as a stoichiometric bioscavenger of nerve agents is well established. However, wide use is currently limited by production and purification costs. Aiming at identifying an alternative human protein bioscavenger, we looked for an original scaffold candidate by virtual screening of the Protein Data Bank for functional similarity using the "Surfing the Molecules" software (sumo-pbil.ibcp.fr) and a search model based on the BChE active site topology. Besides the expected acetylcholinesterase and butyrylcholinesterase, we identified a set of bile salt activated lipases structures, among which the human pancreatic lipase (hBAL) that shares 34% identity with BChE. We produced the recombinant enzyme in mammalian cells, purified it, and measured the inhibition constants for paraoxon and surrogates of VX, sarin and tabun. We solved the X-ray structure of apo hBAL and conjugates with paraoxon and the surrogates at resolutions in the 2-A range. These structures allow the assessment of hBAL for scavenging nerve agents. They revealed that hBAL has inverted stereoselectivity for the surrogates of nerve agent compared to human cholinesterases. We observed a remarkable flip of the catalytic histidine driven by the chelation of Zn(2+). Dealkylation of the conjugate, aka aging, was solely observed for paraoxon. X-ray structures of human bile-salt activated lipase conjugated to nerve agents surrogates.,Touvrey C, Courageux C, Guillon V, Terreux R, Nachon F, Brazzolotto X Toxicology. 2019 Jan 1;411:15-23. doi: 10.1016/j.tox.2018.10.015. Epub 2018 Oct, 22. PMID:30359675 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cholesterol esterase 3D structures Lipase 3D Structures

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