7ytx | pdb_00007ytx

Crystal structure of TLR8 in complex with its antagonist

spinqualitylabelsall models 7ytx, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ytx is a 2 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 2.9Å Ligands: BMA, JRI, MAN, NAG 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 The sensing of self RNA by the endosomal Toll-like receptors (TLRs) 7 and 8 initiates pathogenic mechanisms underlying the autoimmune disease lupus. A blockade of the TLR7/8 signals may, therefore, be a novel therapeutic intervention for lupus. To test the hypothesis, a novel compound E6742 that blocks TLR7/8 activation was identified. The mode of action of E6742 was investigated by analysis of the tertiary structure of TLR7 and 8 in complex with E6742. The in vitro activities of the compound were examined in cellular systems and its therapeutic potential was evaluated in murine lupus models. Tertiary structures of the extracellular domain of TLR7 and 8 in complex with E6742 showed that E6742 binds specifically and non-covalently to the hydrophobic pocket located at the interface of TLR7 or TLR8 homodimers. E6742 potently and selectively inhibited several TLR7/8-mediated cytokine responses in human PBMC. In two mouse models of lupus, oral dosing of E6742 after the onset of disease suppressed increase in autoantibodies and blocked the advance of organ damage. Collectively, the data show that TLR7/8 activation contributes to disease progression and its blocking by E6742 has potential as a therapeutic intervention for lupus. A novel Toll-like receptor 7/8-specific antagonist E6742 ameliorates clinically relevant disease parameters in murine models of lupus.,Ishizaka ST, Hawkins L, Chen Q, Tago F, Yagi T, Sakaniwa K, Zhang Z, Shimizu T, Shirato M Eur J Pharmacol. 2023 Oct 15;957:175962. doi: 10.1016/j.ejphar.2023.175962. Epub , 2023 Aug 5. PMID:37544422 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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