7RC9

Crystal structure of human TLR8 ectodomain bound to small molecule antagonist 21

Summary for 7RC9

• Entry DOI: 10.2210/pdb7rc9/pdb
• Descriptor: 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)-[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, ... (7 entities in total)
• Functional Keywords: toll-like receptor, pattern recognition receptor, pathogen-associated molecular patterns, innate immunity, endosomal receptor, rna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 194116.87

Authors

Critton, D.A. (deposition date: 2021-07-07, release date: 2022-05-04, Last modification date: 2024-10-30)

Primary citation

Sreekantha, R.K.,Mussari, C.P.,Dodd, D.S.,Pasunoori, L.,Hegde, S.,Posy, S.L.,Critton, D.,Ruepp, S.,Subramanian, M.,Salter-Cid, L.M.,Tagore, D.M.,Sarodaya, S.,Dudhgaonkar, S.,Poss, M.A.,Schieven, G.L.,Carter, P.H.,Macor, J.E.,Dyckman, A.J.
Identification of 2-Pyridinylindole-Based Dual Antagonists of Toll-like Receptors 7 and 8 (TLR7/8).
Acs Med.Chem.Lett., 13:812-818, 2022

PubMed Abstract: The toll-like receptors (TLRs) play key roles in activation of the innate immune system. Aberrant activation of TLR7 and TLR8 pathways can occur in the context of autoimmune disorders due to the elevated presence and recognition of self-RNA as activating ligands. Control of this unintended activation via inhibition of TLR7/8 signaling holds promise for the treatment of diseases such as psoriasis, arthritis, and lupus. Optimization of a 2-pyridinylindole series of compounds led to the identification of potent dual inhibitors of TLR7 and TLR8, which demonstrated good selectivity against TLR9 and other family members. The in vitro characterization and in vivo evaluation in rodent pharmacokinetic/pharmacodynamic and efficacy studies of BMS-905 is detailed, along with structural information obtained through X-ray cocrystallographic studies.

PubMed: 35586440
DOI: 10.1021/acsmedchemlett.2c00049

Experimental method

X-RAY DIFFRACTION (2.76 Å)