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- PDB-7ytx: Crystal structure of TLR8 in complex with its antagonist -

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Basic information

Entry
Database: PDB / ID: 7ytx
TitleCrystal structure of TLR8 in complex with its antagonist
ComponentsToll-like receptor 8
KeywordsIMMUNE SYSTEM / Toll-like receptor 8 / inhibitor
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 / positive regulation of interferon-alpha production / immunoglobulin mediated immune response ...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 / positive regulation of interferon-alpha production / immunoglobulin mediated immune response / canonical NF-kappaB signal transduction / 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 / positive regulation of interleukin-6 production / cellular response to mechanical stimulus / 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 / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / Leucine-rich repeat, SDS22-like subfamily / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype ...TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / Leucine-rich repeat, SDS22-like subfamily / TIR domain profile. / 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
Similarity search - Domain/homology
Chem-JRI / Toll-like receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsShimizu, T. / Sakaniwa, K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Pharmacol. / Year: 2023
Title: A novel Toll-like receptor 7/8-specific antagonist E6742 ameliorates clinically relevant disease parameters in murine models of lupus.
Authors: Ishizaka, S.T. / Hawkins, L. / Chen, Q. / Tago, F. / Yagi, T. / Sakaniwa, K. / Zhang, Z. / Shimizu, T. / Shirato, M.
History
DepositionAug 16, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)195,39828
Polymers185,6712
Non-polymers9,72726
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14670 Å2
ΔGint134 kcal/mol
Surface area65560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)145.640, 97.570, 143.810
Angle α, β, γ (deg.)90.00, 104.95, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein / Non-polymers , 2 types, 4 molecules AB

#1: Protein Toll-like receptor 8 /


Mass: 92835.367 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TLR8, UNQ249/PRO286 / Production host: Drosophila (fruit flies) / References: UniProt: Q9NR97
#6: Chemical ChemComp-JRI / (2R,6R)-4-(8-cyanoquinolin-5-yl)-N-[(3S,4R)-4-fluoranylpyrrolidin-3-yl]-6-methyl-morpholine-2-carboxamide


Mass: 383.419 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C20H22FN5O2 / Feature type: SUBJECT OF INVESTIGATION

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Sugars , 5 types, 24 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D- ...alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[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: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_c6-e1_e3-f1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}}}}}}LINUCSPDB-CARE
#3: 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-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-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: 1235.105 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-3DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3/a4-b1_b4-c1_c3-d1_c6-f1_d2-e1_f3-g1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}}}}}}LINUCSPDB-CARE
#5: 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.: 1
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
#7: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 18 / 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

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Details

Has ligand of interestY

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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: 2.66 Å3/Da / Density % sol: 53.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 18% PEG 3350, 0.2M calcium chloride, 0.1M Tris-HCl pH 8.0, 20% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→49.06 Å / Num. obs: 43346 / % possible obs: 100 % / Redundancy: 181.4 % / CC1/2: 0.998 / Net I/σ(I): 13
Reflection shellResolution: 2.9→3.01 Å / Num. unique obs: 4550 / CC1/2: 0.845

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WYX

5wyx


Resolution: 2.9→43.35 Å / SU ML: 0.49 / Cross valid method: THROUGHOUT / σ(F): 1.42 / Phase error: 32.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2956 2213 5.11 %
Rwork0.22 --
obs0.2239 43325 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.9→43.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12067 0 641 0 12708
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913043
X-RAY DIFFRACTIONf_angle_d1.79517697
X-RAY DIFFRACTIONf_dihedral_angle_d17.675029
X-RAY DIFFRACTIONf_chiral_restr0.212185
X-RAY DIFFRACTIONf_plane_restr0.032195
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-2.960.39091420.38572559X-RAY DIFFRACTION100
2.96-3.030.36841460.36952574X-RAY DIFFRACTION100
3.03-3.110.38771480.34482517X-RAY DIFFRACTION100
3.11-3.190.36751350.29022540X-RAY DIFFRACTION100
3.19-3.290.3421370.27462564X-RAY DIFFRACTION100
3.29-3.390.35361290.27422587X-RAY DIFFRACTION100
3.39-3.510.28941380.23462546X-RAY DIFFRACTION100
3.51-3.650.30181310.2172571X-RAY DIFFRACTION100
3.65-3.820.30011430.19732556X-RAY DIFFRACTION100
3.82-4.020.30471320.20452566X-RAY DIFFRACTION100
4.02-4.270.28661380.1982545X-RAY DIFFRACTION100
4.27-4.60.26251480.18612586X-RAY DIFFRACTION100
4.6-5.060.27061180.18362577X-RAY DIFFRACTION100
5.07-5.80.31461410.20672603X-RAY DIFFRACTION100
5.8-7.30.27811400.19692586X-RAY DIFFRACTION100
7.3-43.350.24391470.1962635X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.50190.14390.2951.04720.34111.09160.01110.14170.27510.1141-0.01860.1407-0.0928-0.151-0.00010.2416-0.049-0.01790.90530.08250.408747.9710.20552.666
20.7634-0.13490.15760.73110.20470.7112-0.00511.1348-0.13040.09860.00320.2635-0.00320.1953-0.02340.26630.0508-0.16321.6385-0.00480.169739.01-24.51617.882
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 32:816 OR RESID 901:910 ) )A32 - 816
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 32:816 OR RESID 901:910 ) )A901 - 910
3X-RAY DIFFRACTION2( CHAIN B AND ( RESID 32:821 OR RESID 901:911 ) )B32 - 821
4X-RAY DIFFRACTION2( CHAIN B AND ( RESID 32:821 OR RESID 901:911 ) )B901 - 911

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