Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands

• DOI: 10.1016/j.celrep.2018.11.081
• Publication Date: 2018-12-18T15:39:47Z
• Authors: Zhikuan Zhang; Umeharu Ohto; Takuma Shibata; Masato Taoka; Yoshio Yamauchi; Ryota Sato; Nikunj M. Shukla; Sunil A. David; Toshiaki Isobe; Kensuke Miyake; Toshiyuki Shimizu
• Keywords: TLR7

Toll-like receptor 7 (TLR7) is an innate immune for single-stranded RNA (ssRNA) and has important roles in infectious diseases. We previously reported that TLR7 shows synergistic activation response to two ligands, guanosine ssRNA. However, the specific ssRNA sequence preference, detailed recognition mode of its ligand, molecular determinants TLR8 selectivity remain unknown. Here, we report on from a large-scale crystallographic study combined with multifaceted approach. reveal successive uridine-containing ssRNAs fully or moderately bind TLR7, whereas single have reduced affinities. also relationships between chemical structures ligands their binding TLR7. demonstrate engineered mutant alters responsiveness TLR7-specific ligands. Finally, identify 2′,3′-cyclic phosphate (2′,3′-cGMP) as possible endogenous ligand greater affinity than guanosine. The abundant structural information will facilitate future development treatments targeting