6V9U

Crystal structure of human TLR8 ectodomain bound to small molecule antagonist 14c

Summary for 6V9U

• Entry DOI: 10.2210/pdb6v9u/pdb
• Descriptor: Toll-like receptor 8, 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, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 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: 194842.52

Authors

Critton, D.A. (deposition date: 2019-12-16, release date: 2020-08-12, Last modification date: 2024-10-23)

Primary citation

Mussari, C.P.,Dodd, D.S.,Sreekantha, R.K.,Pasunoori, L.,Wan, H.,Posy, S.L.,Critton, D.,Ruepp, S.,Subramanian, M.,Watson, A.,Davies, P.,Schieven, G.L.,Salter-Cid, L.M.,Srivastava, R.,Tagore, D.M.,Dudhgaonkar, S.,Poss, M.A.,Carter, P.H.,Dyckman, A.J.
Discovery of Potent and Orally Bioavailable Small Molecule Antagonists of Toll-like Receptors 7/8/9 (TLR7/8/9).
Acs Med.Chem.Lett., 11:1751-1758, 2020

PubMed Abstract: The toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system, responsible for the early detection of foreign or endogenous threat signals. In the context of autoimmunity, the unintended recognition of self-motifs as foreign promotes initiation or propagation of disease. Overactivation of TLR7 and TLR9 have been implicated as factors contributing to autoimmune disorders such as psoriasis, arthritis, and lupus. In our search for small molecule antagonists of TLR7/9, was identified as possessing excellent on-target potency for human TLR7/9 as well as for TLR8, with selectivity against other representative TLR family members. Good pharmacokinetic properties and a relatively balanced potency against TLR7 and TLR9 in mouse systems (systems which lack functional TLR8) made this an excellent in vivo tool compound, and efficacy from oral dosing in preclinical models of autoimmune disease was demonstrated.

PubMed: 32944143
DOI: 10.1021/acsmedchemlett.0c00264

Experimental method

X-RAY DIFFRACTION (2.65 Å)