6td5

Leishmania tarentolae proteasome 20S subunit complexed with LXE408 and bortezomib

spinqualitylabelsall models 6td5, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6td5 is a 20 chain structure with sequence from Leishmania donovani. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.2Å Ligands: BO2, N2E Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9UAB4_LEIDO The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.[RuleBase:RU000551] Publication Abstract from PubMed Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the Leishmania tarentolae proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome. Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.,Nagle A, Biggart A, Be C, Srinivas H, Hein A, Caridha D, Sciotti RJ, Pybus B, Kreishman-Deitrick M, Bursulaya B, Lai YH, Gao MY, Liang F, Mathison CJN, Liu X, Yeh V, Smith J, Lerario I, Xie Y, Chianelli D, Gibney M, Berman A, Chen YL, Jiricek J, Davis LC, Liu X, Ballard J, Khare S, Eggimann FK, Luneau A, Groessl T, Shapiro M, Richmond W, Johnson K, Rudewicz PJ, Rao SPS, Thompson C, Tuntland T, Spraggon G, Glynne RJ, Supek F, Wiesmann C, Molteni V J Med Chem. 2020 Oct 8;63(19):10773-10781. doi: 10.1021/acs.jmedchem.0c00499., Epub 2020 Jul 29. PMID:32667203 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proteasome 3D structures

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