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- PDB-7l6w: SFX structure of the MyD88 TIR domain higher-order assembly -

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Basic information

Entry
Database: PDB / ID: 7l6w
TitleSFX structure of the MyD88 TIR domain higher-order assembly
ComponentsMyeloid differentiation primary response protein MyD88
KeywordsPROTEIN BINDING / SFX / serial femtosecond crystallography / MyD88 / TIR domain / higher-order assembly
Function / homology
Function and homology information


regulation of chemokine (C-X-C motif) ligand 1 production / MyD88 deficiency (TLR5) / TIR domain binding / ATP-dependent histone chaperone activity / Toll binding / toll-like receptor 5 signaling pathway / induced systemic resistance / regulation of chemokine (C-X-C motif) ligand 2 production / neutrophil-mediated killing of bacterium / leukocyte activation involved in inflammatory response ...regulation of chemokine (C-X-C motif) ligand 1 production / MyD88 deficiency (TLR5) / TIR domain binding / ATP-dependent histone chaperone activity / Toll binding / toll-like receptor 5 signaling pathway / induced systemic resistance / regulation of chemokine (C-X-C motif) ligand 2 production / neutrophil-mediated killing of bacterium / leukocyte activation involved in inflammatory response / response to molecule of fungal origin / positive regulation of lymphocyte proliferation / response to peptidoglycan / toll-like receptor 8 signaling pathway / positive regulation of interleukin-23 production / regulation of neutrophil migration / IRAK4 deficiency (TLR5) / establishment of endothelial intestinal barrier / MyD88 dependent cascade initiated on endosome / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / MyD88 cascade initiated on plasma membrane / cellular response to oxidised low-density lipoprotein particle stimulus / Toll signaling pathway / Toll-like receptor binding / DEx/H-box helicases activate type I IFN and inflammatory cytokines production / toll-like receptor TLR6:TLR2 signaling pathway / interleukin-33-mediated signaling pathway / neutrophil activation involved in immune response / microglia differentiation / RIP-mediated NFkB activation via ZBP1 / interleukin-1 receptor binding / positive regulation of cytokine production involved in inflammatory response / MyD88 deficiency (TLR2/4) / death receptor binding / interleukin-1-mediated signaling pathway / IRAK4 deficiency (TLR2/4) / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of macrophage cytokine production / MyD88-dependent toll-like receptor signaling pathway / 3'-UTR-mediated mRNA stabilization / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / extrinsic component of plasma membrane / skin development / type I interferon-mediated signaling pathway / response to amine / defense response to protozoan / positive regulation of NLRP3 inflammasome complex assembly / positive regulation of interleukin-17 production / immunoglobulin mediated immune response / positive regulation of type I interferon production / phagocytosis / response to amino acid / positive regulation of chemokine production / JNK cascade / signaling adaptor activity / p75NTR recruits signalling complexes / response to interleukin-1 / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of interleukin-1 beta production / positive regulation of interleukin-8 production / positive regulation of smooth muscle cell proliferation / positive regulation of JNK cascade / positive regulation of NF-kappaB transcription factor activity / positive regulation of interleukin-6 production / cellular response to mechanical stimulus / Interleukin-1 signaling / positive regulation of tumor necrosis factor production / PIP3 activates AKT signaling / ER-Phagosome pathway / cellular response to lipopolysaccharide / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of inflammatory response / response to ethanol / defense response to virus / molecular adaptor activity / gene expression / positive regulation of canonical NF-kappaB signal transduction / cell surface receptor signaling pathway / endosome membrane / defense response to Gram-positive bacterium / defense response to bacterium / innate immune response / apoptotic process / positive regulation of gene expression / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Myeloid differentiation primary response protein MyD88 / MyD88, death domain / TIR domain / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Death domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain ...Myeloid differentiation primary response protein MyD88 / MyD88, death domain / TIR domain / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Death domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Death-like domain superfamily
Similarity search - Domain/homology
Myeloid differentiation primary response protein MyD88
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FREE ELECTRON LASER / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsClabbers, M.T.B. / Holmes, S. / Muusse, T.W. / Vajjhala, P. / Thygesen, S.J. / Malde, A.K. / Hunter, D.J.B. / Croll, T.I. / Flueckiger, L. / Nanson, J.D. ...Clabbers, M.T.B. / Holmes, S. / Muusse, T.W. / Vajjhala, P. / Thygesen, S.J. / Malde, A.K. / Hunter, D.J.B. / Croll, T.I. / Flueckiger, L. / Nanson, J.D. / Rahaman, M.H. / Aquila, A. / Hunter, M.S. / Liang, M. / Yoon, C.H. / Zhao, J. / Zatsepin, N.A. / Abbey, B. / Sierecki, E. / Gambin, Y. / Stacey, K.J. / Darmanin, C. / Kobe, B. / Xu, H. / Ve, T.
Funding support Australia, 1items
OrganizationGrant numberCountry
Australian Research Council (ARC)CE140100011 Australia
CitationJournal: Nat Commun / Year: 2021
Title: MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography.
Authors: Max T B Clabbers / Susannah Holmes / Timothy W Muusse / Parimala R Vajjhala / Sara J Thygesen / Alpeshkumar K Malde / Dominic J B Hunter / Tristan I Croll / Leonie Flueckiger / Jeffrey D ...Authors: Max T B Clabbers / Susannah Holmes / Timothy W Muusse / Parimala R Vajjhala / Sara J Thygesen / Alpeshkumar K Malde / Dominic J B Hunter / Tristan I Croll / Leonie Flueckiger / Jeffrey D Nanson / Md Habibur Rahaman / Andrew Aquila / Mark S Hunter / Mengning Liang / Chun Hong Yoon / Jingjing Zhao / Nadia A Zatsepin / Brian Abbey / Emma Sierecki / Yann Gambin / Katryn J Stacey / Connie Darmanin / Bostjan Kobe / Hongyi Xu / Thomas Ve /
Abstract: MyD88 and MAL are Toll-like receptor (TLR) adaptors that signal to induce pro-inflammatory cytokine production. We previously observed that the TIR domain of MAL (MAL) forms filaments in vitro and ...MyD88 and MAL are Toll-like receptor (TLR) adaptors that signal to induce pro-inflammatory cytokine production. We previously observed that the TIR domain of MAL (MAL) forms filaments in vitro and induces formation of crystalline higher-order assemblies of the MyD88 TIR domain (MyD88). These crystals are too small for conventional X-ray crystallography, but are ideally suited to structure determination by microcrystal electron diffraction (MicroED) and serial femtosecond crystallography (SFX). Here, we present MicroED and SFX structures of the MyD88 assembly, which reveal a two-stranded higher-order assembly arrangement of TIR domains analogous to that seen previously for MAL. We demonstrate via mutagenesis that the MyD88 assembly interfaces are critical for TLR4 signaling in vivo, and we show that MAL promotes unidirectional assembly of MyD88. Collectively, our studies provide structural and mechanistic insight into TLR signal transduction and allow a direct comparison of the MicroED and SFX techniques.
History
DepositionDec 24, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 10, 2021Provider: repository / Type: Initial release
Revision 1.1May 26, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Aug 16, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_related_exp_data_set
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 18, 2023Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Myeloid differentiation primary response protein MyD88


Theoretical massNumber of molelcules
Total (without water)16,2081
Polymers16,2081
Non-polymers00
Water39622
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)100.400, 31.500, 54.500
Angle α, β, γ (deg.)90.000, 107.400, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Myeloid differentiation primary response protein MyD88


Mass: 16207.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MYD88 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q99836
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1029868

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Sample preparation

CrystalDensity Matthews: 2.31 Å3/Da / Density % sol: 46.65 %
Crystal growTemperature: 310 K / Method: batch mode
Details: MAL TIR (0.5-3 micromolar) was incubated with MyD88 TIR domain (60-100 micromolar) in 10 millimolar HEPES at pH 7.5-8, 150 millimolar NaCl at 298-310K.

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Data collection

DiffractionMean temperature: 300 K / Ambient temp details: Room temperature / Serial crystal experiment: Y
Diffraction sourceSource: FREE ELECTRON LASER / Site: SLAC LCLS / Beamline: CXI / Wavelength: 1.314 Å
DetectorType: CS-PAD CXI-1 / Detector: PIXEL / Date: Dec 17, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.314 Å / Relative weight: 1
ReflectionResolution: 2.3→30.94 Å / Num. obs: 7118 / % possible obs: 95.8 % / Redundancy: 1 % / CC1/2: 0.9 / Net I/σ(I): 2.6
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 1 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 560 / CC1/2: 0.36 / % possible all: 78.1
Serial crystallography sample deliveryDescription: GDVN / Method: injection
Serial crystallography sample delivery injectionCarrier solvent: buffer / Crystal conc.: 750 / Flow rate: 20 µL/min
Serial crystallography data reductionFrame hits: 13528 / Frames indexed: 4725 / Frames total: 1029868

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0258refinement
REFMACv5phasing
Aimlessdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7BEQ

7beq


Resolution: 2.3→30.94 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.894 / SU ML: 0.409 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.302 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.288 712 10.1 %RANDOM
Rwork0.2327 ---
obs0.2384 6352 94.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 65.83 Å2 / Biso mean: 38.208 Å2 / Biso min: 19.17 Å2
Baniso -1Baniso -2Baniso -3
1-0.3 Å20 Å21.14 Å2
2--0 Å2-0 Å2
3----0.85 Å2
Refinement stepCycle: final / Resolution: 2.3→30.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1134 0 0 22 1156
Biso mean---33.94 -
Num. residues----138
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0131191
X-RAY DIFFRACTIONr_bond_other_d0.0020.0171143
X-RAY DIFFRACTIONr_angle_refined_deg1.1911.6531609
X-RAY DIFFRACTIONr_angle_other_deg1.0551.5812651
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2995141
X-RAY DIFFRACTIONr_dihedral_angle_2_deg27.4242065
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.17915227
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.9221512
X-RAY DIFFRACTIONr_chiral_restr0.0440.2155
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021301
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02275
X-RAY DIFFRACTIONr_rigid_bond_restr0.39932334
LS refinement shellResolution: 2.3→2.36 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.498 32 -
Rwork0.443 353 -
all-385 -
obs--74.18 %
Refinement TLS params.Method: refined / Origin x: 15.0932 Å / Origin y: 2.168 Å / Origin z: 11.5879 Å
111213212223313233
T0.1184 Å2-0.0063 Å2-0.0911 Å2-0.0055 Å20.0002 Å2--0.0822 Å2
L1.5776 °2-0.1098 °2-0.1313 °2-3.6027 °20.3681 °2--2.369 °2
S0.0151 Å °-0.0592 Å °-0.0162 Å °0.0643 Å °-0.0887 Å °0.1566 Å °-0.0414 Å °0.0379 Å °0.0737 Å °

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