3WN4

Crystal structure of human TLR8 in complex with DS-877

3WN4 の概要

• エントリーDOI: 10.2210/pdb3wn4/pdb
• 分子名称: 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)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 97150.45

構造登録者

Tanji, H.,Ohto, U.,Shimizu, T. (登録日: 2013-12-02, 公開日: 2014-02-19, 最終更新日: 2024-11-06)

主引用文献

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

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: 24474703
DOI: 10.1002/cmdc.201300573

実験手法

X-RAY DIFFRACTION (1.81 Å)