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- PDB-8pfi: Crystal structure of human TLR8 in complex with compound 34 -

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Basic information

Entry
Database: PDB / ID: 8pfi
TitleCrystal structure of human TLR8 in complex with compound 34
ComponentsToll-like receptor 8
KeywordsIMMUNE SYSTEM / TLR8 / toll-like receptor / immune
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-YHG / Toll-like receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.785 Å
AuthorsFaller, M. / Zink, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases.
Authors: Alper, P. / Betschart, C. / Andre, C. / Boulay, T. / Cheng, D. / Deane, J. / Faller, M. / Feifel, R. / Glatthar, R. / Han, D. / Hemmig, R. / Jiang, T. / Knoepfel, T. / Maginnis, J. / ...Authors: Alper, P. / Betschart, C. / Andre, C. / Boulay, T. / Cheng, D. / Deane, J. / Faller, M. / Feifel, R. / Glatthar, R. / Han, D. / Hemmig, R. / Jiang, T. / Knoepfel, T. / Maginnis, J. / Mutnick, D. / Pei, W. / Ruzzante, G. / Syka, P. / Zhang, G. / Zhang, Y. / Zink, F. / Zipfel, G. / Hawtin, S. / Junt, T. / Michellys, P.Y.
History
DepositionJun 16, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 30, 2023Group: 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

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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)193,15222
Polymers184,6162
Non-polymers8,53620
Water8,971498
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12140 Å2
ΔGint131 kcal/mol
Surface area61490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)164.593, 86.942, 153.489
Angle α, β, γ (deg.)90, 120.63, 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, 500 molecules

#5: Chemical ChemComp-YHG / (3~{S})-~{N}-[4-[[5-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)-3-methyl-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridin-1-yl]methyl]-1-bicyclo[2.2.2]octanyl]morpholine-3-carboxamide


Mass: 532.680 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H40N8O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 498 / 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: 2.56 Å3/Da / Density % sol: 51.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1M BIS-TRIS PH5.5, 0.2M AMMONIUM ACETATE, 25%(W/V)PEG3350

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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: Mar 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.79→66.04 Å / Num. obs: 46433 / % possible obs: 98.92 % / Redundancy: 3.5 % / CC1/2: 1 / Net I/σ(I): 16.07
Reflection shellResolution: 2.79→2.89 Å / Num. unique obs: 4593 / CC1/2: 0.791

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata reduction
Aimlessdata scaling
autoBUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.785→66.04 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.9 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.358
RfactorNum. reflection% reflectionSelection details
Rfree0.2498 2372 -RANDOM
Rwork0.216 ---
obs0.2178 46411 99 %-
Displacement parametersBiso mean: 76.7 Å2
Baniso -1Baniso -2Baniso -3
1--7.3222 Å20 Å2-2.9953 Å2
2---6.7233 Å20 Å2
3---14.0455 Å2
Refine analyzeLuzzati coordinate error obs: 0.4 Å
Refinement stepCycle: LAST / Resolution: 2.785→66.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11630 0 568 503 12701
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00512492HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.7917055HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4423SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2084HARMONIC5
X-RAY DIFFRACTIONt_it12492HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1774SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact9006SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.15
X-RAY DIFFRACTIONt_other_torsion16
LS refinement shellResolution: 2.79→2.8 Å
RfactorNum. reflection% reflection
Rfree0.334 39 -
Rwork0.273 --
obs--98.73 %
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)
11.00040.3639-0.20420.8767-0.04671.6744-0.02110.0203-0.22620.02030.0405-0.2672-0.2262-0.2672-0.0194-0.17590.0542-0.0257-0.07720.0266-0.0957-64.231837.1054169.8195
20.6440.149-0.12460.921-0.21751.329-0.05490.0420.11990.0420.04180.27320.11990.27320.01320.00250.06280.0637-0.1538-0.0261-0.0608-26.872816.5276157.2857
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A31 - 818
2X-RAY DIFFRACTION1{ A|* }A1001 - 1020
3X-RAY DIFFRACTION2{ B|* }B31 - 818
4X-RAY DIFFRACTION2{ B|* }B1001 - 1020

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