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4g8a

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Revision as of 19:47, 4 August 2016

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

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:	, , , , ,
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.^[1] [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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Schmidt M, Raghavan B, Muller V, Vogl T, Fejer G, Tchaptchet S, Keck S, Kalis C, Nielsen PJ, Galanos C, Roth J, Skerra A, Martin SF, Freudenberg MA, Goebeler M. Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol. 2010 Sep;11(9):814-9. doi: 10.1038/ni.1919. Epub 2010 Aug 15. PMID:20711192 doi:10.1038/ni.1919
↑ Ohto U, Yamakawa N, Akashi-Takamura S, Miyake K, Shimizu T. Structural analyses of human Toll-like receptor 4 polymorphisms D299G and T399I. J Biol Chem. 2012 Nov 23;287(48):40611-7. doi: 10.1074/jbc.M112.404608. Epub 2012, Oct 10. PMID:23055527 doi:10.1074/jbc.M112.404608

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4g8a"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human TLR4 polymorphic variant D299G and T399I in complex with MD-2 and LPS==
 <StructureSection load='4g8a' size='340' side='right' caption='[[4g8a]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4g8a]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G8A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G8A FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4g8a]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G8A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G8A FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DAO:LAURIC+ACID'>DAO</scene>, <scene name='pdbligand=KDO:3-DEOXY-D-MANNO-OCT-2-ULOSONIC+ACID'>KDO</scene>, <scene name='pdbligand=LP4:2-DEOXY-3-O-[(3R)-3-HYDROXYTETRADECANOYL]-2-{[(3R)-3-HYDROXYTETRADECANOYL]AMINO}-4-O-PHOSPHONO-BETA-D-GLUCOPYRANOSE'>LP4</scene>, <scene name='pdbligand=LP5:(R)-((2R,3S,4R,5R,6R)-3-HYDROXY-2-(HYDROXYMETHYL)-5-((R)-3-HYDROXYTETRADECANAMIDO)-6-(PHOSPHONOOXY)TETRAHYDRO-2H-PYRAN-4-YL)+3-HYDROXYTETRADECANOATE'>LP5</scene>, <scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TLR4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), LY96, ESOP1, MD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TLR4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), LY96, ESOP1, MD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4g8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g8a OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4g8a RCSB], [http://www.ebi.ac.uk/pdbsum/4g8a PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4g8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g8a OCA], [http://pdbe.org/4g8a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g8a RCSB], [http://www.ebi.ac.uk/pdbsum/4g8a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4g8a ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4g8a" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 26: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Ohto, U]]
 [[Category: Shimizu, T]]

4g8a

From Proteopedia

Revision as of 19:47, 4 August 2016

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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