6j04 | pdb_00006j04

Crystal structure of full length human LC3B delta G120 mutant (2_125)

spinqualitylabelsall models 6j04, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6j04 is a 4 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 1.899Å Ligands: SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MLP3B_HUMAN Involved in formation of autophagosomal vacuoles (autophagosomes). Publication Abstract from PubMed Accumulation of mutant proteins is a major cause of many diseases (collectively called proteopathies), and lowering the level of these proteins can be useful for treatment of these diseases. We hypothesized that compounds that interact with both the autophagosome protein microtubule-associated protein 1A/1B light chain 3 (LC3)(1) and the disease-causing protein may target the latter for autophagic clearance. Mutant huntingtin protein (mHTT) contains an expanded polyglutamine (polyQ) tract and causes Huntington's disease, an incurable neurodegenerative disorder(2). Here, using small-molecule-microarray-based screening, we identified four compounds that interact with both LC3 and mHTT, but not with the wild-type HTT protein. Some of these compounds targeted mHTT to autophagosomes, reduced mHTT levels in an allele-selective manner, and rescued disease-relevant phenotypes in cells and in vivo in fly and mouse models of Huntington's disease. We further show that these compounds interact with the expanded polyQ stretch and could lower the level of mutant ataxin-3 (ATXN3), another disease-causing protein with an expanded polyQ tract(3). This study presents candidate compounds for lowering mHTT and potentially other disease-causing proteins with polyQ expansions, demonstrating the concept of lowering levels of disease-causing proteins using autophagosome-tethering compounds. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds.,Li Z, Wang C, Wang Z, Zhu C, Li J, Sha T, Ma L, Gao C, Yang Y, Sun Y, Wang J, Sun X, Lu C, Difiglia M, Mei Y, Ding C, Luo S, Dang Y, Ding Y, Fei Y, Lu B Nature. 2019 Nov;575(7781):203-209. doi: 10.1038/s41586-019-1722-1. Epub 2019 Oct, 30. PMID:31666698 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Microtubule-associated protein 3D structures

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