7zyj | pdb_00007zyj

Leishmania tarentolae proteasome 20S subunit in complex with compound 2

spinqualitylabelsall models 7zyj, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7zyj is a 20 chain structure with sequence from Leishmania tarentolae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.7Å Ligands: KFC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A640KZP5_LEITA 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 Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient K(p) as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios (K(p,uu)) to cure a CNS disease such as HAT. Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).,Koester DC, Marx VM, Williams S, Jiricek J, Dauphinais M, Rene O, Miller SL, Zhang L, Patra D, Chen YL, Cheung H, Gable J, Lakshminarayana SB, Osborne C, Galarneau JR, Kulkarni U, Richmond W, Bretz A, Xiao L, Supek F, Wiesmann C, Honnappa S, Be C, Maser P, Kaiser M, Ritchie R, Barrett MP, Diagana TT, Sarko C, Rao SPS J Med Chem. 2022 Sep 8;65(17):11776-11787. doi: 10.1021/acs.jmedchem.2c00791. , Epub 2022 Aug 22. PMID:35993839 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proteasome 3D structures

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