3WN4
Crystal structure of human TLR8 in complex with DS-877
Summary for 3WN4
| Entry DOI | 10.2210/pdb3wn4/pdb |
| Descriptor | Toll-like receptor 8, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(2-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total) |
| Functional Keywords | leucine rich repeat, rna, glycosylation, innate immunity, rna recognition, ssrnar, structure-based ligand design, tlr8-specific agonist, vaccine adjuvants, antiviral-antitumor drug binding, immune system |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 97150.45 |
| Authors | Tanji, H.,Ohto, U.,Shimizu, T. (deposition date: 2013-12-02, release date: 2014-02-19, Last modification date: 2024-11-06) |
| Primary citation | Kokatla, H.P.,Sil, D.,Tanji, H.,Ohto, U.,Malladi, S.S.,Fox, L.M.,Shimizu, T.,David, S.A. Structure-based design of novel human Toll-like receptor 8 agonists. Chemmedchem, 9:719-723, 2014 Cited by PubMed Abstract: 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 μM). 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. PubMed: 24474703DOI: 10.1002/cmdc.201300573 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.81 Å) |
Structure validation
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