7CRF

Crystal structure of human TLR8 in complex with CU-CPD107

Summary for 7CRF

• Entry DOI: 10.2210/pdb7crf/pdb
• Descriptor: Toll-like receptor 8, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]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, ... (10 entities in total)
• Functional Keywords: immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 196905.83

Authors

Sakaniwa, K.,Tanji, H.,Ohto, U.,Shimizu, T. (deposition date: 2020-08-13, release date: 2021-06-23, Last modification date: 2024-10-09)

Primary citation

Yang, Y.,Csakai, A.,Jiang, S.,Smith, C.,Tanji, H.,Huang, J.,Jones, T.,Sakaniwa, K.,Broadwell, L.,Shi, C.,Soti, S.,Ohto, U.,Fang, Y.,Shen, S.,Deng, F.,Shimizu, T.,Yin, H.
Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists.
Nat Commun, 12:4351-4351, 2021

PubMed Abstract: Small-molecule modulators of TLR8 have drawn much interests as it plays pivotal roles in the innate immune response to single-stranded RNAs (ssRNAs) derived from viruses. However, their clinical uses are limited because they can invoke an uncontrolled, global inflammatory response. The efforts described herein culminate in the fortuitous discovery of a tetrasubstituted imidazole CU-CPD107 which inhibits R848-induced TLR8 signaling. In stark contrast, CU-CPD107 shows unexpected synergistic agonist activities in the presence of ssRNA, while CU-CPD107 alone is unable to influence TLR8 signaling. CU-CPD107's unique, dichotomous behavior sheds light on a way to approach TLR agonists. CU-CPD107 offers the opportunity to avoid the undesired, global inflammation side effects that have rendered imidazoquinolines clinically irrelevant, providing an insight for the development of antiviral drugs.

PubMed: 34272380
DOI: 10.1038/s41467-021-24536-4

Experimental method

X-RAY DIFFRACTION (2.89 Å)