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- PDB-8wo1: Cryo-EM Structure of Human TLR4/MD-2/DLAM5 Complex -

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Basic information

Entry
Database: PDB / ID: 8wo1
TitleCryo-EM Structure of Human TLR4/MD-2/DLAM5 Complex
Components
  • Lymphocyte antigen 96
  • Toll-like receptor 4
KeywordsIMMUNE SYSTEM / Innate immune system / Toll-like receptors / TLR4 agonist / Vaccine adjuvants / Disaccharide-based Lipid A Mimetics
Function / homology
Function and homology information


detection of fungus / nitric oxide production involved in inflammatory response / MHC class II biosynthetic process / positive regulation of cellular response to macrophage colony-stimulating factor stimulus / lipopolysaccharide immune receptor activity / positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway / positive regulation of matrix metallopeptidase secretion / Toll-like receptor 4 binding / lipopolysaccharide receptor complex / regulation of dendritic cell cytokine production ...detection of fungus / nitric oxide production involved in inflammatory response / MHC class II biosynthetic process / positive regulation of cellular response to macrophage colony-stimulating factor stimulus / lipopolysaccharide immune receptor activity / positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway / positive regulation of matrix metallopeptidase secretion / Toll-like receptor 4 binding / lipopolysaccharide receptor complex / regulation of dendritic cell cytokine production / detection of lipopolysaccharide / MyD88-independent TLR4 cascade / intestinal epithelial structure maintenance / I-kappaB phosphorylation / TRIF-mediated programmed cell death / negative regulation of interleukin-23 production / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / cellular response to oxidised low-density lipoprotein particle stimulus / wound healing involved in inflammatory response / B cell proliferation involved in immune response / Toll Like Receptor 4 (TLR4) Cascade / Caspase activation via Death Receptors in the presence of ligand / nucleotide-binding oligomerization domain containing 1 signaling pathway / positive regulation of interleukin-1 production / positive regulation of stress-activated MAPK cascade / Regulation of TLR by endogenous ligand / positive regulation of lipopolysaccharide-mediated signaling pathway / macrophage activation / TRIF-dependent toll-like receptor signaling pathway / astrocyte development / microglia differentiation / positive regulation of macrophage activation / nucleotide-binding oligomerization domain containing 2 signaling pathway / NAD+ nucleotidase, cyclic ADP-ribose generating / positive regulation of MHC class II biosynthetic process / negative regulation of interleukin-17 production / positive regulation of cytokine production involved in inflammatory response / positive regulation of platelet activation / MyD88 deficiency (TLR2/4) / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of extrinsic apoptotic signaling pathway / negative regulation of cold-induced thermogenesis / MyD88-dependent toll-like receptor signaling pathway / positive regulation of macrophage cytokine production / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / toll-like receptor signaling pathway / positive regulation of reactive oxygen species biosynthetic process / T-helper 1 type immune response / positive regulation of NLRP3 inflammasome complex assembly / RSV-host interactions / positive regulation of smooth muscle cell migration / negative regulation of osteoclast differentiation / : / cellular response to platelet-derived growth factor stimulus / positive regulation of interferon-alpha production / cellular response to lipoteichoic acid / negative regulation of interleukin-6 production / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of interleukin-10 production / negative regulation of type II interferon production / phagocytic cup / negative regulation of tumor necrosis factor production / phagocytosis / stress-activated MAPK cascade / positive regulation of B cell proliferation / positive regulation of chemokine production / JNK cascade / lipopolysaccharide-mediated signaling pathway / ruffle / nitric oxide biosynthetic process / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / positive regulation of interleukin-12 production / positive regulation of interferon-beta production / ERK1 and ERK2 cascade / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / IKK complex recruitment mediated by RIP1 / positive regulation of interleukin-1 beta production / positive regulation of interleukin-8 production / lipopolysaccharide binding / positive regulation of JNK cascade / positive regulation of smooth muscle cell proliferation / positive regulation of MAP kinase activity / Heme signaling / negative regulation of ERK1 and ERK2 cascade / cellular response to type II interferon / positive regulation of inflammatory response / positive regulation of interleukin-6 production / cellular response to mechanical stimulus / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of type II interferon production / cellular response to amyloid-beta / positive regulation of nitric oxide biosynthetic process / positive regulation of tumor necrosis factor production / transmembrane signaling receptor activity / positive regulation of NF-kappaB transcription factor activity / signaling receptor activity
Similarity search - Function
Lymphocyte antigen 96 / ML domain / MD-2-related lipid-recognition domain / Domain involved in innate immunity and lipid metabolism. / Toll-like receptor / Leucine rich repeat 4 / Leucine Rich repeats (2 copies) / Leucine Rich repeat / TIR domain / Cysteine-rich flanking region, C-terminal ...Lymphocyte antigen 96 / ML domain / MD-2-related lipid-recognition domain / Domain involved in innate immunity and lipid metabolism. / Toll-like receptor / Leucine rich repeat 4 / Leucine Rich repeats (2 copies) / Leucine Rich repeat / TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / TIR domain profile. / Leucine-rich repeat, SDS22-like subfamily / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Immunoglobulin E-set
Similarity search - Domain/homology
: / (3R)-3-(dodecanoyloxy)tetradecanoic acid / : / Chem-GP4 / : / Lymphocyte antigen 96 / Toll-like receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.24 Å
AuthorsFu, Y. / Kim, H. / Kim, H.M.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
Other governmentInstitute for Basic Science, IBS Korea, Republic Of
CitationJournal: To Be Published
Title: Structural insight on tailored modulation of TLR4-mediated pro-inflammatory response by disaccharide Lipid A mimetics
Authors: Fu, Y. / Kim, H.
History
DepositionOct 6, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Toll-like receptor 4
C: Lymphocyte antigen 96
B: Toll-like receptor 4
D: Lymphocyte antigen 96
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,59726
Polymers170,4494
Non-polymers8,14922
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 4 molecules ABCD

#1: Protein Toll-like receptor 4


Mass: 68838.328 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TLR4 / Cell line (production host): High Five / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O00206
#2: Protein Lymphocyte antigen 96


Mass: 16385.941 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LY96 / Cell line (production host): High Five / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: B3Y6A6

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Sugars , 5 types, 16 molecules

#3: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#6: Sugar ChemComp-GP4 / 2-amino-2-deoxy-4-O-phosphono-alpha-D-glucopyranose / GLUCOSAMINE 4-PHOSPHATE / N-acetyl-4-O-phosphono-alpha-D-glucosamine / 2-amino-2-deoxy-4-O-phosphono-alpha-D-glucose / 2-amino-2-deoxy-4-O-phosphono-D-glucose / 2-amino-2-deoxy-4-O-phosphono-glucose


Type: D-saccharide, alpha linking / Mass: 259.151 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H14NO8P / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
a-D-GlcpN4PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#9: Sugar ChemComp-X6N / [(2~{R},3~{S},4~{R},5~{S})-2-(hydroxymethyl)-5-methoxy-4,6-bis(oxidanyl)oxan-3-yl] dihydrogen phosphate


Type: D-saccharide, alpha linking / Mass: 274.162 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H15O9P / Feature type: SUBJECT OF INVESTIGATION

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Non-polymers , 3 types, 6 molecules

#7: Chemical ChemComp-2IL / (3R)-3-(dodecanoyloxy)tetradecanoic acid


Mass: 426.673 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H50O4 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-0IL / (3R)-3-(tetradecanoyloxy)tetradecanoic acid


Mass: 454.726 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H54O4 / Feature type: SUBJECT OF INVESTIGATION
#10: Chemical ChemComp-A1L01 / (3~{S})-3-decanoyloxytetradecanoic acid


Mass: 398.620 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H46O4 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human TLR4/MD2/DLAM5 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTrisTris1
2200 mMsodium chlorideNaCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 10mA / Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Calibrated magnification: 58963 X / Nominal defocus max: 1900 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 67.7 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9930

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Processing

EM software
IDNameVersionCategory
7PHENIX1.16_3549:model fitting
9cryoSPARC4.2.1initial Euler assignment
10cryoSPARC4.2.1final Euler assignment
11cryoSPARC4.2.1classification
12cryoSPARC4.2.13D reconstruction
13PHENIX1.16_3549:model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 795271 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 3FXI

3fxi


Accession code: 3FXI / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00612648
ELECTRON MICROSCOPYf_angle_d0.80217060
ELECTRON MICROSCOPYf_dihedral_angle_d8.5067566
ELECTRON MICROSCOPYf_chiral_restr0.0521992
ELECTRON MICROSCOPYf_plane_restr0.0042132

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