4qc0 | pdb_00004qc0

Crystal structure of human TLR8 in complex with XG-1-236

spinqualitylabelsall models 4qc0, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4qc0 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. Ligands: BMA, MAN, NAG, XG1 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) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-a-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing "heuristics" to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity. Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure-Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds.,Yoo E, Salunke DB, Sil D, Guo X, Salyer AC, Hermanson AR, Kumar M, Malladi SS, Balakrishna R, Thompson WH, Tanji H, Ohto U, Shimizu T, David SA J Med Chem. 2014 Oct 9;57(19):7955-70. doi: 10.1021/jm500744f. Epub 2014 Sep 17. PMID:25192394 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Toll-like Receptor 3D structures

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