4QC0

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

4QC0 の概要

• エントリーDOI: 10.2210/pdb4qc0/pdb
• 関連するPDBエントリー: 4QBZ
• 分子名称: Toll-like receptor 8, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-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, glycosylation, innate immunity, rna recognition, ssrna, rna receptor, structure-based ligand design, tlr8 and tlr7 agonist, vaccine adjuvants, antiviral and antitumor drug binding, rna binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 189765.69

構造登録者

Tanji, H.,Ohto, U.,Shimizu, T. (登録日: 2014-05-09, 公開日: 2014-10-22, 最終更新日: 2024-10-30)

主引用文献

Yoo, E.,Salunke, D.B.,Sil, D.,Guo, X.,Salyer, A.C.D.,Hermanson, A.R.,Kumar, M.,Malladi, S.S.,Balakrishna, R.,Thompson, W.H.,Tanji, H.,Ohto, U.,Shimizu, T.,David, S.A.
Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure-Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds
J.Med.Chem., 57:7955-7970, 2014

PubMed Abstract: 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-à-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.

PubMed: 25192394
DOI: 10.1021/jm500744f

実験手法

X-RAY DIFFRACTION (2.1 Å)