4g8a | pdb_00004g8a

Crystal structure of human TLR4 polymorphic variant D299G and T399I in complex with MD-2 and LPS

spinqualitylabelsall models 4g8a, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4g8a is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DAO, KDO, LP4, LP5, MYR, NAG Gene: TLR4 (HUMAN), LY96, ESOP1, MD2 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [TLR4_HUMAN] Genetic variation in TLR4 is associated with age-related macular degeneration type 10 (ARMD10) [MIM:611488]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Function [TLR4_HUMAN] Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Also involved in LPS-independent inflammatory responses triggered by Ni(2+). These responses require non-conserved histidines and are, therefore, species-specific. [LY96_HUMAN] Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria. Enhances TLR4-dependent activation of NF-kappa-B. Cells expressing both MD2 and TLR4, but not TLR4 alone, respond to LPS. Publication Abstract from PubMed BACKGROUND: TLR4 polymorphism replacing Asp-299 with Gly and Thr-399 with Ile (D299G/T399I) causes LPS hyporesponsiveness. RESULTS: TLR4(SNPs).MD-2.LPS exhibits an agonistic 2:2:2 architecture. Local structural differences were observed around D299G, but not around T399I, SNP site. CONCLUSION: These local differences cause the modulation of surface properties of TLR4, which may affect ligand binding. SIGNIFICANCE: This study provides structural evidence of the functionality of the mutant TLR4 carrying the SNPs. 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 A 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. Structural analyses of human Toll-like receptor 4 polymorphisms D299G and T399I.,Ohto U, Yamakawa N, Akashi-Takamura S, Miyake K, Shimizu T J Biol Chem. 2012 Nov 23;287(48):40611-7. doi: 10.1074/jbc.M112.404608. Epub 2012, Oct 10. PMID:23055527 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Toll-like Receptors

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