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- PDB-6wml: Human TLR8 bound to the potent agonist, GS-9688 (Selgantolimod) -

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Basic information

Entry
Database: PDB / ID: 6wml
TitleHuman TLR8 bound to the potent agonist, GS-9688 (Selgantolimod)
ComponentsToll-like receptor 8
KeywordsIMMUNE SYSTEM / Selgantolimod / Toll-like Receptor / Immune Activator / Receptor agonist
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
alpha-D-mannopyranose / Chem-U57 / Toll-like receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsAppleby, T.C. / Perry, J.K. / Mish, M. / Villasenor, A.G. / Mackman, R.L.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B.
Authors: Mackman, R.L. / Mish, M. / Chin, G. / Perry, J.K. / Appleby, T. / Aktoudianakis, V. / Metobo, S. / Pyun, P. / Niu, C. / Daffis, S. / Yu, H. / Zheng, J. / Villasenor, A.G. / Zablocki, J. / ...Authors: Mackman, R.L. / Mish, M. / Chin, G. / Perry, J.K. / Appleby, T. / Aktoudianakis, V. / Metobo, S. / Pyun, P. / Niu, C. / Daffis, S. / Yu, H. / Zheng, J. / Villasenor, A.G. / Zablocki, J. / Chamberlain, J. / Jin, H. / Lee, G. / Suekawa-Pirrone, K. / Santos, R. / Delaney 4th, W.E. / Fletcher, S.P.
History
DepositionApr 21, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 3, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
C: Toll-like receptor 8
D: Toll-like receptor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)385,50246
Polymers371,3414
Non-polymers14,16042
Water7,638424
1
A: Toll-like receptor 8
B: Toll-like receptor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)192,80725
Polymers185,6712
Non-polymers7,13723
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12960 Å2
ΔGint89 kcal/mol
Surface area58790 Å2
MethodPISA
2
C: Toll-like receptor 8
D: Toll-like receptor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)192,69421
Polymers185,6712
Non-polymers7,02419
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13100 Å2
ΔGint92 kcal/mol
Surface area57460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.816, 141.575, 171.263
Angle α, β, γ (deg.)90.000, 90.413, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Toll-like receptor 8 /


Mass: 92835.367 Da / Num. of mol.: 4
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 , 7 types, 38 molecules

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


Type: oligosaccharide / Mass: 383.349 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-2/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-Manp]{}}LINUCSPDB-CARE
#4: 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.: 7
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
#5: 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.: 2
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
#6: 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.: 1
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
#7: Sugar
ChemComp-MAN / alpha-D-mannopyranose / alpha-D-mannose / D-mannose / mannose / Mannose


Type: D-saccharide, alpha linking / Mass: 180.156 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Formula: C6H12O6
IdentifierTypeProgram
DManpaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
a-D-mannopyranoseCOMMON NAMEGMML 1.0
a-D-ManpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
ManSNFG CARBOHYDRATE SYMBOLGMML 1.0
#8: 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.: 16
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, 428 molecules

#9: Chemical
ChemComp-U57 / (2R)-2-[(2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino]-2-methylhexan-1-ol


Mass: 293.340 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H20FN5O / Feature type: SUBJECT OF INVESTIGATION
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 424 / 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: 2.84 Å3/Da / Density % sol: 56.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 4% (w/v) PEG 3350 0.2 M potassium formate 0.1 M sodium citrate, pH 5.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9762 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2→47.86 Å / Num. obs: 270193 / % possible obs: 98.1 % / Redundancy: 3.2 % / Biso Wilson estimate: 48.39 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.06 / Net I/σ(I): 17.44
Reflection shellResolution: 2.5→2.65 Å / Num. unique obs: 22744 / CC1/2: 0.84 / Rrim(I) all: 0.498 / % possible all: 98.9

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3W3K

3w3k


Resolution: 2.5→47.86 Å / SU ML: 0.3222 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.9066
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.255 3827 1.42 %
Rwork0.2109 266366 -
obs0.2115 270193 95.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.09 Å2
Refinement stepCycle: LAST / Resolution: 2.5→47.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms22413 0 927 424 23764
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002323830
X-RAY DIFFRACTIONf_angle_d0.542232421
X-RAY DIFFRACTIONf_chiral_restr0.04213900
X-RAY DIFFRACTIONf_plane_restr0.00324086
X-RAY DIFFRACTIONf_dihedral_angle_d10.7663556
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.530.33311470.29789897X-RAY DIFFRACTION95.14
2.53-2.570.3161400.29089998X-RAY DIFFRACTION97.45
2.57-2.60.35481400.286710067X-RAY DIFFRACTION97.67
2.6-2.640.36441410.272410109X-RAY DIFFRACTION97.51
2.64-2.680.31591460.262410021X-RAY DIFFRACTION97.39
2.68-2.720.30211340.253510068X-RAY DIFFRACTION97.31
2.72-2.760.29971330.23919926X-RAY DIFFRACTION97.24
2.76-2.810.3071460.235510059X-RAY DIFFRACTION97.2
2.81-2.860.26811440.23299892X-RAY DIFFRACTION96.84
2.86-2.920.29151480.238510051X-RAY DIFFRACTION96.98
2.92-2.980.26891490.23949941X-RAY DIFFRACTION96.79
2.98-3.040.30771440.2389877X-RAY DIFFRACTION96.49
3.04-3.110.36651460.235610049X-RAY DIFFRACTION96.74
3.11-3.190.28751440.23429902X-RAY DIFFRACTION96.43
3.19-3.280.2821420.24039880X-RAY DIFFRACTION96.39
3.28-3.370.29361440.22689962X-RAY DIFFRACTION96.04
3.37-3.480.25751410.21819836X-RAY DIFFRACTION95.74
3.48-3.610.28671400.21189903X-RAY DIFFRACTION95.67
3.61-3.750.25541420.19379765X-RAY DIFFRACTION95.29
3.75-3.920.22721400.18529778X-RAY DIFFRACTION94.89
3.92-4.130.2351350.17949777X-RAY DIFFRACTION94.7
4.13-4.390.22151450.17159629X-RAY DIFFRACTION94.01
4.39-4.720.18451410.17399643X-RAY DIFFRACTION93.62
4.72-5.20.22871400.17599722X-RAY DIFFRACTION93.83
5.2-5.950.24771340.29556X-RAY DIFFRACTION93.31
5.95-7.490.24031450.21239681X-RAY DIFFRACTION94
7.49-47.860.19631360.2149377X-RAY DIFFRACTION90.96

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