PDBsum entry 4qbz

RNA binding protein

PDB id: 4qbz

Contents

Protein chains

754 a.a.

Ligands

NAG-NAG-BMA-MAN-BMA

NAG-NAG ×2

NAG-NAG-BMA ×2

NAG-NAG-BMA-MAN

NAG ×11

D80 ×2

Waters ×506

PDB id:

4qbz

Name:

RNA binding protein

Title:

Crystal structure of human tlr8 in complex with ds-802

Structure:

Toll-like receptor 8. Chain: a, b. Fragment: unp residues 27-827. Synonym: tlr8. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tlr8. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227. Expression_system_cell: drosophila s2

Resolution:

2.00Å R-factor: 0.212 R-free: 0.264

Authors:

H.Tanji,U.Ohto,T.Shimizu

Key ref:

E.Yoo et al. (2014). Determinants of activity at human Toll-like receptors 7 and 8: quantitative structure-activity relationship (QSAR) of diverse heterocyclic scaffolds. J Med Chem, 57, 7955-7970. PubMed id: 25192394 DOI: 10.1021/jm500744f

Date:

09-May-14 Release date: 22-Oct-14

Protein chains

Q9NR97  (TLR8_HUMAN) -  Toll-like receptor 8 from Homo sapiens

Seq: 1041 a.a.

Struc: 754 a.a.

DOI no: 10.1021/jm500744f

J Med Chem 57:7955-7970 (2014)

PubMed id: 25192394

Determinants of activity at human Toll-like receptors 7 and 8: quantitative structure-activity relationship (QSAR) of diverse heterocyclic scaffolds.

E.Yoo, D.B.Salunke, D.Sil, X.Guo, A.C.Salyer, A.R.Hermanson, M.Kumar, S.S.Malladi, R.Balakrishna, W.H.Thompson, H.Tanji, U.Ohto, T.Shimizu, S.A.David.

ABSTRACT

Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing "heuristics" to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity.