3wn4

Crystal structure of human TLR8 in complex with DS-877

spinqualitylabelsall models 3wn4, resolution 1.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3wn4 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BMA, D87, NAG, MAN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [TLR8_HUMAN] Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Publication Abstract from PubMed Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds might be promising candidate vaccine adjuvants. Recently, a C2-butyl furo[2,3-c]quinoline was reported with purely TLR8 agonistic activity. This compound was successfully co-crystallized with the human TLR8 ectodomain, and the co-crystal structure revealed ligand-induced reorganization of the binding pocket of TLR8. The loss of a key hydrogen bond between the oxygen atom of the furanyl ring of the agonist and Thr 574 in TLR8 suggested that the furan ring is dispensable. Employing a disconnection strategy, 3- and 4-substituted aminoquinolines were investigated. Focused structure-based ligand design studies led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist (EC50 =0.2 muM). Preliminary evaluation of this compound in ex vivo human blood assay systems revealed that it retains prominent cytokine-inducing activity. Together, these results indicate the suitability of this compound as a novel vaccine adjuvant, warranting further investigation. Structure-Based Design of Novel Human Toll-like Receptor 8 Agonists.,Kokatla HP, Sil D, Tanji H, Ohto U, Malladi SS, Fox LM, Shimizu T, David SA ChemMedChem. 2014 Jan 28. doi: 10.1002/cmdc.201300573. PMID:24474703 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Toll-like Receptor 3D structures

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