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- PDB-4r6a: Crystal structure of human TLR8 in complex with Hybrid-2 -

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Basic information

Entry
Database: PDB / ID: 4r6a
TitleCrystal structure of human TLR8 in complex with Hybrid-2
ComponentsToll-like receptor 8
KeywordsRNA BINDING PROTEIN / RNA recognition / ssRNA / Leucine rich repeat / RNA Receptor / innate immunity / Glycosylation / Secreted / Structure-based Ligand Design / vaccine adjuvants / Antiviral and Antitumor Drug Binding
Function / homology
Function and homology information


Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 8 signaling pathway / negative regulation of interleukin-12 production / endolysosome membrane / positive regulation of innate immune response / Trafficking and processing of endosomal TLR / pattern recognition receptor activity / toll-like receptor signaling pathway / immunoglobulin mediated immune response / canonical NF-kappaB signal transduction ...Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 8 signaling pathway / negative regulation of interleukin-12 production / endolysosome membrane / positive regulation of innate immune response / Trafficking and processing of endosomal TLR / pattern recognition receptor activity / toll-like receptor signaling pathway / immunoglobulin mediated immune response / canonical NF-kappaB signal transduction / positive regulation of interferon-alpha production / positive regulation of interferon-beta production / positive regulation of interleukin-1 beta production / positive regulation of interleukin-8 production / regulation of protein phosphorylation / response to virus / cellular response to mechanical stimulus / positive regulation of interleukin-6 production / positive regulation of type II interferon production / double-stranded RNA binding / signaling receptor activity / defense response to virus / single-stranded RNA binding / endosome membrane / inflammatory response / external side of plasma membrane / Golgi membrane / innate immune response / endoplasmic reticulum membrane / SARS-CoV-2 activates/modulates innate and adaptive immune responses / DNA binding / RNA binding / identical protein binding / plasma membrane
Similarity search - Function
TIR domain / Leucine Rich Repeat / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / Leucine-rich repeat, LRR (right-handed beta-alpha superhelix) / Ribonuclease Inhibitor / Leucine-rich repeat, SDS22-like subfamily / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain ...TIR domain / Leucine Rich Repeat / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / Leucine-rich repeat, LRR (right-handed beta-alpha superhelix) / Ribonuclease Inhibitor / Leucine-rich repeat, SDS22-like subfamily / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Alpha-Beta Horseshoe / 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 / Alpha Beta
Similarity search - Domain/homology
Chem-HB2 / Toll-like receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsTanji, H. / Ohto, U. / Shimizu, T.
CitationJournal: To be Published
Title: Hybrid-2: AnImidazoquinoline Dual Toll-like receptor 7/8 Agonist that Potently Activates Cytokine Production by Human Newborn and Adult Leukocytes
Authors: Ganapathi, L. / Haren, S.V. / Dowling, D.J. / Bergelson, I. / Shukla, N.M. / Malladi, S.S. / Balakrishna, R. / Tanji, H. / Ohto, U. / Shimizu, T. / David, S.A. / Levy, O.
History
DepositionAug 22, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_unobs_or_zero_occ_atoms / struct_asym / struct_conn / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Toll-like receptor 8
B: Toll-like receptor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)192,35120
Polymers185,6712
Non-polymers6,68018
Water7,242402
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13750 Å2
ΔGint104 kcal/mol
Surface area59980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.143, 122.211, 107.778
Angle α, β, γ (deg.)90.00, 91.13, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Toll-like receptor 8


Mass: 92835.367 Da / Num. of mol.: 2 / Fragment: UNP residues 27-827
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TLR8, UNQ249/PRO286 / Cell (production host): S2 CELL / Production host: DROSOPHILA MELANOGASTER (fruit fly) / References: UniProt: Q9NR97

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Sugars , 4 types, 16 molecules

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


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#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-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#4: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
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

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Non-polymers , 2 types, 404 molecules

#6: Chemical ChemComp-HB2 / 1-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol


Mass: 312.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H24N4O
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 402 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.52 Å3/Da / Density % sol: 51.25 %
Crystal growTemperature: 293 K / pH: 4.9
Details: 10%(w/v) PEG3350, 0.1M sodium citrate pH 4.9, 0.3M potassium formate, temperature 293K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NE3A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Jun 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 89651 / % possible obs: 87.1 % / Redundancy: 2.7 % / Rsym value: 0.1 / Net I/σ(I): 17

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.8.0073refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→26.09 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.914 / SU B: 6.755 / SU ML: 0.171 / Cross valid method: THROUGHOUT / ESU R: 0.259 / ESU R Free: 0.219 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25932 4733 5 %RANDOM
Rwork0.20084 ---
obs0.20375 80433 86.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.476 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å20 Å2-0.01 Å2
2---0 Å20 Å2
3---0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.1→26.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11973 0 441 402 12816
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01912707
X-RAY DIFFRACTIONr_bond_other_d0.0010.0212096
X-RAY DIFFRACTIONr_angle_refined_deg1.652.00917270
X-RAY DIFFRACTIONr_angle_other_deg0.786327722
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.87651477
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.67824.883598
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.816152165
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7231562
X-RAY DIFFRACTIONr_chiral_restr0.0910.22038
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213998
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022919
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.863.6775935
X-RAY DIFFRACTIONr_mcbond_other2.863.6765934
X-RAY DIFFRACTIONr_mcangle_it4.3225.4987403
X-RAY DIFFRACTIONr_mcangle_other4.3215.4987404
X-RAY DIFFRACTIONr_scbond_it3.394.0056772
X-RAY DIFFRACTIONr_scbond_other3.3894.0056772
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.3335.8649868
X-RAY DIFFRACTIONr_long_range_B_refined7.45129.20914391
X-RAY DIFFRACTIONr_long_range_B_other7.44729.20414319
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.09→2.144 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.347 350 -
Rwork0.32 6261 -
obs--83.04 %

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