6WML
Human TLR8 bound to the potent agonist, GS-9688 (Selgantolimod)
Summary for 6WML
| Entry DOI | 10.2210/pdb6wml/pdb |
| Descriptor | Toll-like receptor 8, 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, ... (10 entities in total) |
| Functional Keywords | selgantolimod, toll-like receptor, immune activator, receptor agonist, immune system |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 385501.73 |
| Authors | Appleby, T.C.,Perry, J.K.,Mish, M.,Villasenor, A.G.,Mackman, R.L. (deposition date: 2020-04-21, release date: 2021-02-03, Last modification date: 2024-11-06) |
| Primary citation | Mackman, R.L.,Mish, M.,Chin, G.,Perry, J.K.,Appleby, T.,Aktoudianakis, V.,Metobo, S.,Pyun, P.,Niu, C.,Daffis, S.,Yu, H.,Zheng, J.,Villasenor, A.G.,Zablocki, J.,Chamberlain, J.,Jin, H.,Lee, G.,Suekawa-Pirrone, K.,Santos, R.,Delaney 4th, W.E.,Fletcher, S.P. Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B. J.Med.Chem., 63:10188-10203, 2020 Cited by PubMed Abstract: Toll-like receptor 8 (TLR8) recognizes pathogen-derived single-stranded RNA fragments to trigger innate and adaptive immune responses. Chronic hepatitis B (CHB) is associated with a dysfunctional immune response, and therefore a selective TLR8 agonist may be an effective treatment option. Structure-based optimization of a dual TLR7/8 agonist led to the identification of the selective TLR8 clinical candidate ()-2-((2-amino-7-fluoropyrido[3,2-]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (GS-9688, ()-). Potent TLR8 agonism (IL-12p40 EC = 220 nM) and >100-fold TLR7 selectivity (IFN-α EC > 50 μM) was observed in human peripheral blood mononuclear cells (PBMCs). The TLR8-ectodomain:()- complex confirmed TLR8 binding and a direct ligand interaction with TLR8 residue Asp545. Oral ()- had good absorption and high first pass clearance in preclinical species. A reduction in viral markers was observed in HBV-infected primary human hepatocytes treated with media from PBMCs stimulated with ()-, supporting the clinical development of ()- for the treatment of CHB. PubMed: 32407112DOI: 10.1021/acs.jmedchem.0c00100 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
Download full validation report
