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- PDB-4qc0: Crystal structure of human TLR8 in complex with XG-1-236 -

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Basic information

Entry
Database: PDB / ID: 4qc0
TitleCrystal structure of human TLR8 in complex with XG-1-236
ComponentsToll-like receptor 8
KeywordsRNA BINDING PROTEIN / Leucine rich repeat / Glycosylation / innate immunity / RNA recognition / ssRNA / RNA Receptor / Structure-based Ligand Design / TLR8 and TLR7 agonist / 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 / double-stranded RNA binding / positive regulation of type II interferon production / 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
2-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine / 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: J.Med.Chem. / Year: 2014
Title: Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure-Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds
Authors: Yoo, E. / Salunke, D.B. / Sil, D. / Guo, X. / Salyer, A.C.D. / Hermanson, A.R. / Kumar, M. / Malladi, S.S. / Balakrishna, R. / Thompson, W.H. / Tanji, H. / Ohto, U. / Shimizu, T. / David, S.A.
History
DepositionMay 9, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 22, 2014Provider: repository / Type: Initial release
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...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 / 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 / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.src_method / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _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)189,76613
Polymers185,6712
Non-polymers4,09511
Water3,171176
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10680 Å2
ΔGint68 kcal/mol
Surface area59660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.510, 149.220, 85.830
Angle α, β, γ (deg.)90.00, 103.50, 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 / TLR8


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 / Cell (production host): Drosophila S2 / Production host: Drosophila Melanogaster (fruit fly) / References: UniProt: Q9NR97

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Sugars , 3 types, 9 molecules

#2: 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.: 3
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
#3: 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
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5
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, 178 molecules

#5: Chemical ChemComp-XG1 / 2-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine


Mass: 240.304 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H16N4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 176 / 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: 2.4 Å3/Da / Density % sol: 48.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.2
Details: 12%(w/v) PEG3350, 0.1M sodium citrate, 0.3M potassium formate, pH 5.2, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 21, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→83.46 Å / Num. obs: 96489 / % possible obs: 88.8 % / Redundancy: 2.8 % / Rsym value: 0.11 / Net I/σ(I): 6

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.8.0069refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→83.46 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.904 / SU B: 7.963 / SU ML: 0.202 / Cross valid method: THROUGHOUT / ESU R: 0.28 / ESU R Free: 0.23 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27137 4509 5 %RANDOM
Rwork0.21336 ---
obs0.21631 85502 88.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.087 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å20.02 Å2
2---0.02 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.1→83.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11984 0 273 176 12433
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01912537
X-RAY DIFFRACTIONr_bond_other_d0.0020.0211980
X-RAY DIFFRACTIONr_angle_refined_deg1.6841.99717031
X-RAY DIFFRACTIONr_angle_other_deg0.87327475
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.27451483
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.92524.882594
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.415152165
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.2241562
X-RAY DIFFRACTIONr_chiral_restr0.0880.21988
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02113971
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022911
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_it2.4433.5775956
X-RAY DIFFRACTIONr_mcbond_other2.4433.5765955
X-RAY DIFFRACTIONr_mcangle_it3.7145.3537431
X-RAY DIFFRACTIONr_mcangle_other3.7145.3547432
X-RAY DIFFRACTIONr_scbond_it2.6873.836581
X-RAY DIFFRACTIONr_scbond_other2.6863.836581
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.2445.6269601
X-RAY DIFFRACTIONr_long_range_B_refined6.29228.33413891
X-RAY DIFFRACTIONr_long_range_B_other6.28928.32413866
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.155 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.346 332 -
Rwork0.331 6240 -
obs--87.84 %

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