PDBsum entry 5awb

Immune system

PDB id: 5awb

Contents

Protein chain

748 a.a.

Ligands

NAG-NAG-BMA-MAN

NAG-NAG

NAG-NAG-BMA

M0A

NAG ×3

Waters ×190

PDB id:

5awb

Name:

Immune system

Title:

Crystal structure of human tlr8 in complex with n1-3-aminomethylbenzyl (meta-amine)

Structure:

Toll-like receptor 8. Chain: a. Fragment: extracellular domain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tlr8. Expressed in: drosophila. Expression_system_taxid: 7215.

Resolution:

2.10Å R-factor: 0.204 R-free: 0.259

Authors:

H.Tanji,U.Ohto,T.Shimizu

Key ref:

M.Beesu et al. (2015). Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity. J Med Chem, 58, 7833-7849. PubMed id: 26351878 DOI: 10.1021/acs.jmedchem.5b01087

Date:

03-Jul-15 Release date: 23-Sep-15

Protein chain

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

Seq: 1041 a.a.

Struc: 748 a.a.

DOI no: 10.1021/acs.jmedchem.5b01087

J Med Chem 58:7833-7849 (2015)

PubMed id: 26351878

Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity.

M.Beesu, G.Caruso, A.C.Salyer, K.K.Khetani, D.Sil, M.Weerasinghe, H.Tanji, U.Ohto, T.Shimizu, S.A.David.

ABSTRACT

Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by "designing in" functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization.