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- EMDB-37677: Cryo-EM Structure of Human TLR4/MD-2/DLAM5 Complex -

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Basic information

Entry
Database: EMDB / ID: EMD-37677
TitleCryo-EM Structure of Human TLR4/MD-2/DLAM5 Complex
Map data
Sample
  • Complex: human TLR4/MD2/DLAM5 complex
    • Protein or peptide: Toll-like receptor 4
    • Protein or peptide: Lymphocyte antigen 96
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-amino-2-deoxy-4-O-phosphono-alpha-D-glucopyranose
  • Ligand: (3R)-3-(dodecanoyloxy)tetradecanoic acid
  • Ligand: (3R)-3-(tetradecanoyloxy)tetradecanoic acid
  • Ligand: [(2~{R},3~{S},4~{R},5~{S})-2-(hydroxymethyl)-5-methoxy-4,6-bis(oxidanyl)oxan-3-yl] dihydrogen phosphate
  • Ligand: (3~{S})-3-decanoyloxytetradecanoic acid
KeywordsInnate immune system / Toll-like receptors / TLR4 agonist / Vaccine adjuvants / Disaccharide-based Lipid A Mimetics / IMMUNE SYSTEM
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
Lymphocyte antigen 96 / Toll-like receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.24 Å
AuthorsFu Y / Kim H / Kim HM
Funding support Korea, Republic Of, 1 items
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, 2023-
Header (metadata) releaseOct 9, 2024-
Map releaseOct 9, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37677.png

Downloads & links

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Map

FileDownload / File: emd_37677.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 400 pix.
= 339.2 Å		0.85 Å/pix.
x 400 pix.
= 339.2 Å		0.85 Å/pix.
x 400 pix.
= 339.2 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.848 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-0.99471515 - 2.5605571
Average (Standard dev.)-0.0009451687 (±0.04305869)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 339.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37677_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_37677_half_map_2.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human TLR4/MD2/DLAM5 complex

EntireName: human TLR4/MD2/DLAM5 complex
Components
  • Complex: human TLR4/MD2/DLAM5 complex
    • Protein or peptide: Toll-like receptor 4
    • Protein or peptide: Lymphocyte antigen 96
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-amino-2-deoxy-4-O-phosphono-alpha-D-glucopyranose
  • Ligand: (3R)-3-(dodecanoyloxy)tetradecanoic acid
  • Ligand: (3R)-3-(tetradecanoyloxy)tetradecanoic acid
  • Ligand: [(2~{R},3~{S},4~{R},5~{S})-2-(hydroxymethyl)-5-methoxy-4,6-bis(oxidanyl)oxan-3-yl] dihydrogen phosphate
  • Ligand: (3~{S})-3-decanoyloxytetradecanoic acid

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Supramolecule #1: human TLR4/MD2/DLAM5 complex

SupramoleculeName: human TLR4/MD2/DLAM5 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Toll-like receptor 4

MacromoleculeName: Toll-like receptor 4 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 68.838328 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: EPCVEVVPNI TYQCMELNFY KIPDNLPFST KNLDLSFNPL RHLGSYSFFS FPELQVLDLS RCEIQTIEDG AYQSLSHLST LILTGNPIQ SLALGAFSGL SSLQKLVAVE TNLASLENFP IGHLKTLKEL NVAHNLIQSF KLPEYFSNLT NLEHLDLSSN K IQSIYCTD ...String:
EPCVEVVPNI TYQCMELNFY KIPDNLPFST KNLDLSFNPL RHLGSYSFFS FPELQVLDLS RCEIQTIEDG AYQSLSHLST LILTGNPIQ SLALGAFSGL SSLQKLVAVE TNLASLENFP IGHLKTLKEL NVAHNLIQSF KLPEYFSNLT NLEHLDLSSN K IQSIYCTD LRVLHQMPLL NLSLDLSLNP MNFIQPGAFK EIRLHKLTLR NNFDSLNVMK TCIQGLAGLE VHRLVLGEFR NE GNLEKFD KSALEGLCNL TIEEFRLAYL DYYLDDIIDL FNCLTNVSSF SLVSVTIERV KDFSYNFGWQ HLELVNCKFG QFP TLKLKS LKRLTFTSNK GGNAFSEVDL PSLEFLDLSR NGLSFKGCCS QSDFGTTSLK YLDLSFNGVI TMSSNFLGLE QLEH LDFQH SNLKQMSEFS VFLSLRNLIY LDISHTHTRV AFNGIFNGLS SLEVLKMAGN SFQENFLPDI FTELRNLTFL DLSQC QLEQ LSPTAFNSLS SLQVLNMSHN NFFSLDTFPY KCLNSLQVLD YSLNHIMTSK KQELQHFPSS LAFLNLTQND FACTCE HQS FLQWIKDQRQ LLVEVERMEC ATPSDKQGMP VLSLNITCQM NK

UniProtKB: Toll-like receptor 4

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Macromolecule #2: Lymphocyte antigen 96

MacromoleculeName: Lymphocyte antigen 96 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.385941 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
QKQYWVCNSS DASISYTYCD KMQYPISINV NPCIELKGSK GLLHIFYIPR RDLKQLYFNL YITVNTMNLP KRKEVICRGS DDDYSFCRA LKGETVNTTI SFSFKGIKFS KGKYKCVVEA ISGSPEEMLF CLEFVILHQP NSN

UniProtKB: Lymphocyte antigen 96

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #6: 2-amino-2-deoxy-4-O-phosphono-alpha-D-glucopyranose

MacromoleculeName: 2-amino-2-deoxy-4-O-phosphono-alpha-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 2 / Formula: GP4
Molecular weightTheoretical: 259.151 Da
Chemical component information

ChemComp-GP4:
2-amino-2-deoxy-4-O-phosphono-alpha-D-glucopyranose

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Macromolecule #7: (3R)-3-(dodecanoyloxy)tetradecanoic acid

MacromoleculeName: (3R)-3-(dodecanoyloxy)tetradecanoic acid / type: ligand / ID: 7 / Number of copies: 2 / Formula: 2IL
Molecular weightTheoretical: 426.673 Da
Chemical component information

ChemComp-2IL:
(3R)-3-(dodecanoyloxy)tetradecanoic acid

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Macromolecule #8: (3R)-3-(tetradecanoyloxy)tetradecanoic acid

MacromoleculeName: (3R)-3-(tetradecanoyloxy)tetradecanoic acid / type: ligand / ID: 8 / Number of copies: 2 / Formula: 0IL
Molecular weightTheoretical: 454.726 Da

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Macromolecule #9: [(2~{R},3~{S},4~{R},5~{S})-2-(hydroxymethyl)-5-methoxy-4,6-bis(ox...

MacromoleculeName: [(2~{R},3~{S},4~{R},5~{S})-2-(hydroxymethyl)-5-methoxy-4,6-bis(oxidanyl)oxan-3-yl] dihydrogen phosphate
type: ligand / ID: 9 / Number of copies: 2 / Formula: X6N
Molecular weightTheoretical: 274.162 Da

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Macromolecule #10: (3~{S})-3-decanoyloxytetradecanoic acid

MacromoleculeName: (3~{S})-3-decanoyloxytetradecanoic acid / type: ligand / ID: 10 / Number of copies: 2 / Formula: A1L01
Molecular weightTheoretical: 398.62 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
Component:
ConcentrationFormulaName
20.0 mMTrisTris
200.0 mMNaClsodium chloride
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 5 sec. / Details: 10mA
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 9930 / Average electron dose: 67.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated magnification: 58963 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.9000000000000001 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

3fxi

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.24 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.2.1) / Number images used: 795271
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2.1)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.2.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

3fxi


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL
Output model

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

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