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- PDB-7r53: Crystal structure of human TLR8 in complex with Compound 15 -

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Basic information

Entry
Database: PDB / ID: 7r53
TitleCrystal structure of human TLR8 in complex with Compound 15
ComponentsToll-like receptor 8
KeywordsIMMUNE SYSTEM / Toll-like receptor / TLR8
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 / positive regulation of interferon-alpha production ...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 / positive regulation of interferon-alpha production / 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 / 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 / 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-I5N / Toll-like receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.121 Å
AuthorsFaller, M. / Zink, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Structure-Based Optimization of a Fragment-like TLR8 Binding Screening Hit to an In Vivo Efficacious TLR7/8 Antagonist.
Authors: Betschart, C. / Faller, M. / Zink, F. / Hemmig, R. / Blank, J. / Vangrevelinghe, E. / Bourrel, M. / Glatthar, R. / Behnke, D. / Barker, K. / Heizmann, A. / Angst, D. / Nimsgern, P. / ...Authors: Betschart, C. / Faller, M. / Zink, F. / Hemmig, R. / Blank, J. / Vangrevelinghe, E. / Bourrel, M. / Glatthar, R. / Behnke, D. / Barker, K. / Heizmann, A. / Angst, D. / Nimsgern, P. / Jacquier, S. / Junt, T. / Zipfel, G. / Ruzzante, G. / Loetscher, P. / Limonta, S. / Hawtin, S. / Andre, C.B. / Boulay, T. / Feifel, R. / Knoepfel, T.
History
DepositionFeb 10, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1May 4, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)192,84522
Polymers184,6162
Non-polymers8,23020
Water2,504139
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)164.882, 89.065, 152.273
Angle α, β, γ (deg.)90, 120.26, 90
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Toll-like receptor 8 /


Mass: 92307.766 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 melanogaster (fruit fly) / References: UniProt: Q9NR97

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Sugars , 3 types, 18 molecules

#2: Polysaccharide
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...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: 910.823 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 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]{}}}}}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.: 2
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: 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.: 12 / 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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Non-polymers , 2 types, 141 molecules

#5: Chemical ChemComp-I5N / 5-cyclopropyl-6-(2,6-dimethylpyridin-4-yl)-~{N}-[(3~{R},4~{R})-3-fluoranylpiperidin-4-yl]-1~{H}-indazol-3-amine


Mass: 379.474 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26FN5 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 139 / Source method: isolated from a natural source / Formula: H2O

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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: 2.62 Å3/Da / Density % sol: 52.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 20%(w/v) PEG3350, 0.2M Calcium chloride dihydrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 23, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.12→68.48 Å / Num. obs: 32656 / % possible obs: 95.41 % / Redundancy: 3.3 % / CC1/2: 1 / Rmerge(I) obs: 0.062 / Net I/σ(I): 10.06
Reflection shellResolution: 3.12→3.23 Å / Num. unique obs: 3387 / CC1/2: 0.936

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3w3g

3w3g


Resolution: 3.121→68.48 Å / Cor.coef. Fo:Fc: 0.888 / Cor.coef. Fo:Fc free: 0.88 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.504
RfactorNum. reflection% reflectionSelection details
Rfree0.2689 1552 -RANDOM
Rwork0.2378 ---
obs0.2393 32648 95.6 %-
Displacement parametersBiso mean: 101.46 Å2
Baniso -1Baniso -2Baniso -3
1--13.5334 Å20 Å25.5924 Å2
2---24.7811 Å20 Å2
3---38.3145 Å2
Refine analyzeLuzzati coordinate error obs: 0.46 Å
Refinement stepCycle: LAST / Resolution: 3.121→68.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11587 0 546 139 12272
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00512422HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.7316959HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4376SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2075HARMONIC5
X-RAY DIFFRACTIONt_it12422HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1778SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact8791SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion1.95
X-RAY DIFFRACTIONt_other_torsion15.68
LS refinement shellResolution: 3.121→3.14 Å
RfactorNum. reflection% reflection
Rfree0.4057 26 -
Rwork0.3196 --
obs--99.09 %
Refinement TLS params.

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)
11.41870.3878-0.32250.9845-0.19422.59290.04680.0313-0.44510.03130.072-0.542-0.4451-0.542-0.1188-0.23470.1181-0.02130.02060.0451-0.169814.8687-2.246237.6911
21.52590.256-0.140.9317-0.18912.2189-0.0469-0.09290.4302-0.0929-0.06520.37820.43020.37820.1121-0.04860.11910.0125-0.20950.0324-0.069150.9728-23.476225.2357
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A31 - 818
2X-RAY DIFFRACTION1{ A|* }A1001 - 1101
3X-RAY DIFFRACTION2{ B|* }B31 - 818
4X-RAY DIFFRACTION2{ B|* }B1001 - 1101

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