Taxanes inhibit human TLR4 signaling by binding to MD-2

Resman, Nuša; Gradišar, Helena; Vašl, Jožica; Keber, Mateja Manček; Pristovšek, Primož; Jerala, Roman

doi:10.1016/j.febslet.2008.10.037

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Volume 582, Issue 28 , Pages 3929-3934, 26 November 2008

Taxanes inhibit human TLR4 signaling by binding to MD-2

Edited by Giulio Superti-Furga

Nuša Resman
- Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
Helena Gradišar
- Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
Jožica Vašl
- Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
Mateja Manček Keber
- Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
Primož Pristovšek
- Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
Roman Jerala
- Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia
- Corresponding author. Address: Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia. Fax: +386 1 476 0448.

Received 26 August 2008; received in revised form 20 October 2008; accepted 21 October 2008. published online 31 October 2008.

Abstract

LPS is the primary ligand of Toll-like receptor 4, activating it through binding to its accessory protein MD-2. Murine but not human cells expressing MD-2/TLR4 are also activated by paclitaxel. Paclitaxel binds to human MD-2. The binding site of paclitaxel overlaps with the binding site of bis-ANS and LPS, which results in the ability of taxanes to inhibit LPS signaling in the system with human receptors. Circular dichroic spectra of human MD-2 indicated differences in the chemical environment in the presence of paclitaxel and docetaxel. Molecular docking identified the interacting residues of MD-2 and suggests that hydrophobic interactions govern the binding, while the C-3′N group where the paclitaxel and docetaxel differ is exposed on the surface of MD-2.

Keywords: Paclitaxel, Docetaxel, MD-2, Lipopolysaccharide, Toll-like receptor 4