Journal of Biological Chemistry
Volume 287, Issue 48, 23 November 2012, Pages 40611-40617
Journal home page for Journal of Biological Chemistry

Protein Structure and Folding
Structural Analyses of Human Toll-like Receptor 4 Polymorphisms D299G and T399I*

https://doi.org/10.1074/jbc.M112.404608Get rights and content
Under a Creative Commons license
open access

Toll-like receptor 4 (TLR4) and its coreceptor MD-2 recognize bacterial lipopolysaccharide (LPS) and signal the innate immune response. Two single nucleotide polymorphisms (SNPs) of human TLR4, D299G and T399I, have been identified and suggested to be associated with LPS hyporesponsiveness. Moreover, the SNPs have been proposed to be associated with a variety of infectious and noninfectious diseases. However, how the SNPs affect the function of TLR4 remains largely unknown. Here, we report the crystal structure of the human TLR4 (D299G/T399I)·MD-2·LPS complex at 2.4 Å resolution. The ternary complex exhibited an agonistic “m”-shaped 2:2:2 architecture that was similar to that of the human wild type TLR4·MD-2·LPS complex. Local structural differences that might affect the binding of the ligands were observed around D299G, but not around T399I, SNP site.

Crystal Structure
Innate Immunity
Lipopolysaccharide (LPS)
Toll-like Receptors (TLR)
X-ray Crystallography
MD-2
SNPs

Cited by (0)

The atomic coordinates and structure factors (code 4G8A) have been deposited in the Protein Data Bank (http://wwpdb.org/).

*

This work was supported by Grant-in-Aid for Scientific Research (B) and Grant-in-Aid for Scientific Research on Innovative Areas (3106) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

This article contains supplemental Table S1 and Figs. S and S2.