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- PDB-7ber: SFX structure of the MyD88 TIR domain higher-order assembly (solv... -

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Entry
Database: PDB / ID: 7ber
TitleSFX structure of the MyD88 TIR domain higher-order assembly (solved, rebuilt and refined using an identical protocol to the MicroED 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 / cellular response to oxidised low-density lipoprotein particle stimulus / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / MyD88 cascade initiated on plasma membrane / 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 / death receptor binding / positive regulation of cytokine production involved in inflammatory response / MyD88 deficiency (TLR2/4) / extrinsic component of cytoplasmic side of plasma membrane / interleukin-1-mediated signaling pathway / extrinsic component of plasma membrane / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / positive regulation of macrophage cytokine production / 3'-UTR-mediated mRNA stabilization / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / type I interferon-mediated signaling pathway / skin development / defense response to protozoan / positive regulation of NLRP3 inflammasome complex assembly / positive regulation of interleukin-17 production / response to amine / immunoglobulin mediated immune response / response to amino acid / positive regulation of type I interferon production / phagocytosis / positive regulation of chemokine production / JNK cascade / signaling adaptor activity / response to interleukin-1 / p75NTR recruits signalling complexes / 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 interleukin-6 production / Interleukin-1 signaling / cellular response to mechanical stimulus / positive regulation of NF-kappaB transcription factor activity / 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 / gene expression / molecular adaptor activity / defense response to virus / response to ethanol / positive regulation of canonical NF-kappaB signal transduction / cell surface receptor signaling pathway / defense response to Gram-positive bacterium / endosome membrane / 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. / Nanson, J.D. / Rahaman, M.H. ...Clabbers, M.T.B. / Holmes, S. / Muusse, T.W. / Vajjhala, P. / Thygesen, S.J. / Malde, A.K. / Hunter, D.J.B. / Croll, T.I. / 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. / Darmanin, C. / Kobe, B. / Xu, H. / Ve, T.
Funding support Sweden, Australia, 2items
OrganizationGrant numberCountry
Swedish Research Council2017-05333 Sweden
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: PDBE / Processing site: PDBE
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
Revision 1.2Dec 13, 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 1.3Jan 31, 2024Group: 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)17,8341
Polymers17,8341
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area8090 Å2
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
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

#1: Protein Myeloid differentiation primary response protein MyD88


Mass: 17833.854 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

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

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Data collection

DiffractionMean temperature: 300 K / Serial crystal experiment: N
Diffraction sourceSource: FREE ELECTRON LASER / Site: SLAC LCLS / Beamline: CXI / Wavelength: 1.3 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: 1.3 Å / Relative weight: 1
ReflectionResolution: 2.3→30.94 Å / Num. obs: 7118 / % possible obs: 95.8 % / Redundancy: 1 % / Biso Wilson estimate: 32.47 Å2 / 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

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
PHASER2.8.2phasing
CrystFELdata scaling
Aimlessdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4W8G

4w8g


Resolution: 2.3→30.93 Å / SU ML: 0.2669 / Cross valid method: THROUGHOUT / σ(F): 1.91 / Phase error: 39.873 / Stereochemistry target values: CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2806 353 5.01 %
Rwork0.2392 6687 -
obs0.2414 7040 94.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.6 Å2
Refinement stepCycle: LAST / Resolution: 2.3→30.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1133 0 0 0 1133
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00131159
X-RAY DIFFRACTIONf_angle_d0.36961565
X-RAY DIFFRACTIONf_chiral_restr0.0389174
X-RAY DIFFRACTIONf_plane_restr0.0026195
X-RAY DIFFRACTIONf_dihedral_angle_d9.8881713
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.630.40731040.31781966X-RAY DIFFRACTION84.28
2.63-3.320.33721210.29482299X-RAY DIFFRACTION98.9
3.32-30.930.22761280.19722422X-RAY DIFFRACTION99.92

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