3FXI

Crystal structure of the human TLR4-human MD-2-E.coli LPS Ra complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.241 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex

Park, B.S.Song, D.H.Kim, H.M.Choi, B.-S.Lee, H.Lee, J.-O.

(2009) Nature 458: 1191-1195

  • DOI: https://doi.org/10.1038/nature07830
  • Primary Citation of Related Structures:  
    3FXI

  • PubMed Abstract: 

    The lipopolysaccharide (LPS) of Gram negative bacteria is a well-known inducer of the innate immune response. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules. To understand the ligand specificity and receptor activation mechanism of the TLR4-MD-2-LPS complex we determined its crystal structure. LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically. LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2, forming a hydrophobic interaction with the conserved phenylalanines of TLR4. The F126 loop of MD-2 undergoes localized structural change and supports this core hydrophobic interface by making hydrophilic interactions with TLR4. Comparison with the structures of tetra-acylated antagonists bound to MD-2 indicates that two other lipid chains in LPS displace the phosphorylated glucosamine backbone by approximately 5 A towards the solvent area. This structural shift allows phosphate groups of LPS to contribute to receptor multimerization by forming ionic interactions with a cluster of positively charged residues in TLR4 and MD-2. The TLR4-MD-2-LPS structure illustrates the remarkable versatility of the ligand recognition mechanisms employed by the TLR family, which is essential for defence against diverse microbial infection.


  • Organizational Affiliation

    Department of Chemistry, KAIST, Daejeon, 305-701, Korea.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Toll-like receptor 4
A, B
605Homo sapiensMutation(s): 0 
Gene Names: TLR4
UniProt & NIH Common Fund Data Resources
Find proteins for O00206 (Homo sapiens)
Explore O00206 
Go to UniProtKB:  O00206
PHAROS:  O00206
GTEx:  ENSG00000136869 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00206
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Lymphocyte antigen 96
C, D
142Homo sapiensMutation(s): 0 
Gene Names: ESOP1LY96MD-2MD2
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y6Y9 (Homo sapiens)
Explore Q9Y6Y9 
Go to UniProtKB:  Q9Y6Y9
PHAROS:  Q9Y6Y9
GTEx:  ENSG00000154589 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y6Y9
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
L-glycero-alpha-D-manno-heptopyranose-(1-7)-L-glycero-alpha-D-manno-heptopyranose-(1-3)-L-glycero-alpha-D-manno-heptopyranose-(1-5)-[3-deoxy-alpha-D-manno-oct-2-ulopyranosonic acid-(2-4)]3-deoxy-alpha-D-manno-oct-2-ulopyranosonic acid-(2-6)-2-amino-2-deoxy-alpha-D-glucopyranose-(1-6)-2-amino-2-deoxy-alpha-D-glucopyranose
E
7N/A
Glycosylation Resources
GlyTouCan:  G75876QI
GlyCosmos:  G75876QI
Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
F, G, I, J
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
L-glycero-alpha-D-manno-heptopyranose-(1-7)-L-glycero-alpha-D-manno-heptopyranose-(1-3)-L-glycero-alpha-D-manno-heptopyranose-(1-5)-[3-deoxy-alpha-D-manno-oct-2-ulopyranosonic acid-(2-4)]3-deoxy-alpha-D-manno-oct-2-ulopyranosonic acid-(2-6)-2-amino-2-deoxy-beta-D-glucopyranose-(1-6)-2-amino-2-deoxy-alpha-D-glucopyranose
H
7N/A
Glycosylation Resources
GlyTouCan:  G02042LC
GlyCosmos:  G02042LC
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FTT
Query on FTT

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
K [auth A]
L [auth A]
M [auth A]
AA [auth B],
BA [auth B],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
Y [auth B],
Z [auth B]
3-HYDROXY-TETRADECANOIC ACID
C14 H28 O3
ATRNZOYKSNPPBF-CYBMUJFWSA-N
MYR
Query on MYR

Download Ideal Coordinates CCD File 
DA [auth B],
P [auth A]
MYRISTIC ACID
C14 H28 O2
TUNFSRHWOTWDNC-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
IA [auth B]
JA [auth B]
KA [auth B]
MA [auth C]
NA [auth D]
IA [auth B],
JA [auth B],
KA [auth B],
MA [auth C],
NA [auth D],
U [auth A],
V [auth A],
W [auth A]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
DAO
Query on DAO

Download Ideal Coordinates CCD File 
CA [auth B],
O [auth A]
LAURIC ACID
C12 H24 O2
POULHZVOKOAJMA-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
EA [auth B]
FA [auth B]
GA [auth B]
HA [auth B]
Q [auth A]
EA [auth B],
FA [auth B],
GA [auth B],
HA [auth B],
Q [auth A],
R [auth A],
S [auth A],
T [auth A]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
MG
Query on MG

Download Ideal Coordinates CCD File 
LA [auth B],
X [auth A]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.241 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.16α = 90
b = 103.5β = 90
c = 251.81γ = 90
Software Package:
Software NamePurpose
CNSrefinement
PDB_EXTRACTdata extraction
DNAdata collection
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-03
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2012-06-20
    Changes: Non-polymer description
  • Version 1.3: 2020-07-01
    Changes: Advisory, Data collection, Derived calculations
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-11-01
    Changes: Data collection, Database references, Refinement description, Structure summary