6e69 | pdb_00006e69

Ortho-substituted phenyl sulfonyl fluoride and fluorosulfate as potent elastase inhibitory fragments

spinqualitylabelsall models 6e69, resolution 2.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6e69 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 2.33Å Ligands: FUC, HVP, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ELNE_HUMAN Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:162800; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency. Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:202700. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. Function ELNE_HUMAN Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis. Publication Abstract from PubMed Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC50 0.24 muM and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form. SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase.,Zheng Q, Woehl JL, Kitamura S, Santos-Martins D, Smedley CJ, Li G, Forli S, Moses JE, Wolan DW, Sharpless KB Proc Natl Acad Sci U S A. 2019 Sep 17;116(38):18808-18814. doi:, 10.1073/pnas.1909972116. Epub 2019 Sep 4. PMID:31484779 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Elastase 3D structures

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