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- PDB-6zjz: Discovery of M5049: a novel selective TLR7/8 inhibitor for treatm... -

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Basic information

Entry
Database: PDB / ID: 6zjz
TitleDiscovery of M5049: a novel selective TLR7/8 inhibitor for treatment of autoimmunity
ComponentsToll-like receptor 8
KeywordsIMMUNE SYSTEM / LEUCINE RICH REPEAT / RNA / GLYCOSYLATION / INNATE IMMUNITY
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 / 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 / Leucine Rich Repeat / 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 ...TIR domain / Leucine Rich Repeat / 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
FORMIC ACID / Chem-QLH / Toll-like receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.489 Å
AuthorsMusil, D. / Lehman, M. / Strauss, J.
CitationJournal: J.Pharmacol.Exp.Ther. / Year: 2021
Title: Discovery of M5049: A Novel Selective Toll-Like Receptor 7/8 Inhibitor for Treatment of Autoimmunity.
Authors: Vlach, J. / Bender, A.T. / Przetak, M. / Pereira, A. / Deshpande, A. / Johnson, T.L. / Reissig, S. / Tzvetkov, E. / Musil, D. / Morse, N.T. / Haselmayer, P. / Zimmerli, S.C. / Okitsu, S.L. / ...Authors: Vlach, J. / Bender, A.T. / Przetak, M. / Pereira, A. / Deshpande, A. / Johnson, T.L. / Reissig, S. / Tzvetkov, E. / Musil, D. / Morse, N.T. / Haselmayer, P. / Zimmerli, S.C. / Okitsu, S.L. / Walsky, R.L. / Sherer, B.
History
DepositionJun 29, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 30, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _citation_author.name
Revision 1.2Jan 31, 2024Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,94820
Polymers183,1302
Non-polymers7,81818
Water1,72996
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13460 Å2
ΔGint107 kcal/mol
Surface area63780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.362, 98.245, 141.095
Angle α, β, γ (deg.)90.000, 105.640, 90.000
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: 91564.875 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 falleni (fry) / References: UniProt: Q9NR97

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Sugars , 4 types, 15 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D- ...alpha-D-mannopyranose-(1-2)-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: 1072.964 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-6]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-f1_d2-e1WURCSPDB2Glycan 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]{}}}}}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: 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.: 2
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
#5: 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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 9
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 , 3 types, 99 molecules

#6: Chemical ChemComp-QLH / 5-[(3~{R},5~{S})-3-azanyl-5-(trifluoromethyl)piperidin-1-yl]quinoline-8-carbonitrile


Mass: 320.312 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H15F3N4 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CH2O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 96 / 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: 2.67 Å3/Da / Density % sol: 53.88 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 12.5% PEG 3350, 0.2 M K formate, 0.1 M Na citrate, pH 5.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99977 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99977 Å / Relative weight: 1
ReflectionResolution: 2.489→135.87 Å / Num. obs: 53528 / % possible obs: 93 % / Redundancy: 3.4 % / CC1/2: 1 / Rpim(I) all: 0.022 / Rrim(I) all: 0.043 / Net I/σ(I): 18.1
Reflection shellResolution: 2.489→2.681 Å / Num. unique obs: 2677 / CC1/2: 0.556 / Rpim(I) all: 0.553

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (19-MAR-2020)refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
autoPROCdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3WN4

3wn4


Resolution: 2.489→135.87 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.921 / SU R Cruickshank DPI: 1.035 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.782 / SU Rfree Blow DPI: 0.304 / SU Rfree Cruickshank DPI: 0.316
RfactorNum. reflection% reflectionSelection details
Rfree0.2435 2698 5.04 %RANDOM
Rwork0.2037 ---
obs0.2057 53528 93 %-
Displacement parametersBiso max: 150.25 Å2 / Biso mean: 93.66 Å2 / Biso min: 53.35 Å2
Baniso -1Baniso -2Baniso -3
1--0.6779 Å20 Å2-1.2728 Å2
2--1.8061 Å20 Å2
3----1.1282 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.489→135.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11894 0 518 96 12508
Biso mean--95.66 71.06 -
Num. residues----1477
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4554SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2111HARMONIC5
X-RAY DIFFRACTIONt_it12706HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1778SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8405SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d12709HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg17305HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion2.9
X-RAY DIFFRACTIONt_other_torsion17.62
LS refinement shellResolution: 2.49→2.61 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2918 56 5.23 %
Rwork0.2423 1015 -
all0.2447 1071 -
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)
11.046-0.1885-0.08681.0435-0.77141.85490.1311-0.1639-0.0047-0.0788-0.01880.1210.06960.2147-0.1123-0.12370.0618-0.0638-0.0278-0.027-0.1913151.0356-0.438917.2452
22.03480.1740.38381.2115-0.54611.1091-0.0807-0.5034-0.076-0.19660.2684-0.03830.0866-0.0346-0.1877-0.13690.01670.03430.0093-0.0306-0.2006160.077-23.730150.3947
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A31 - 816
2X-RAY DIFFRACTION2{ B|* }B30 - 822

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