6KYA

Crystal structure of human TLR8 in complex TH1027

Summary for 6KYA

• Entry DOI: 10.2210/pdb6kya/pdb
• Descriptor: Toll-like receptor 8, 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, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 192191.03

Authors

Tanji, H.,Sakaniwa, K.,Ohto, U.,Shimizu, T. (deposition date: 2019-09-17, release date: 2020-05-27, Last modification date: 2024-11-06)

Primary citation

Jiang, S.,Tanji, H.,Yin, K.,Zhang, S.,Sakaniwa, K.,Huang, J.,Yang, Y.,Li, J.,Ohto, U.,Shimizu, T.,Yin, H.
Rationally Designed Small-Molecule Inhibitors Targeting an Unconventional Pocket on the TLR8 Protein-Protein Interface.
J.Med.Chem., 63:4117-4132, 2020

PubMed Abstract: Rational designs of small-molecule inhibitors targeting protein-protein interfaces have met little success. Herein, we have designed a series of triazole derivatives with a novel scaffold to specifically intervene with the interaction of TLR8 homomerization. In multiple assays, was identified as a highly potent and specific inhibitor of TLR8. A successful solution of the X-ray crystal structure of TLR8 in complex with provided an in-depth mechanistic insight into its binding mode, validating that was located between two TLR8 monomers and recognized as an unconventional pocket, thereby preventing TLR8 from activation. Further biological evaluations showed that dose-dependently suppressed the TLR8-mediated inflammatory responses in both human monocyte cell lines, peripheral blood mononuclear cells, and rheumatoid arthritis patient specimens, suggesting a strong therapeutic potential against autoimmune diseases.

PubMed: 32233366
DOI: 10.1021/acs.jmedchem.9b02128

Experimental method

X-RAY DIFFRACTION (2.89 Å)