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- PDB-6y6c: TREM2 extracellular domain (19-174) in complex with single-chain ... -

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Basic information

Entry
Database: PDB / ID: 6y6c
TitleTREM2 extracellular domain (19-174) in complex with single-chain variable fragment (scFv-4)
Components
  • Single chain variable
  • Triggering receptor expressed on myeloid cells 2
KeywordsIMMUNE SYSTEM / scFv / complex / receptor / Alzheimer's
Function / homology
Function and homology information


positive regulation of high-density lipoprotein particle clearance / regulation of toll-like receptor 6 signaling pathway / positive regulation of complement activation, classical pathway / detection of lipoteichoic acid / regulation of macrophage inflammatory protein 1 alpha production / regulation of hippocampal neuron apoptotic process / regulation of plasma membrane bounded cell projection organization / : / positive regulation of C-C chemokine receptor CCR7 signaling pathway / excitatory synapse pruning ...positive regulation of high-density lipoprotein particle clearance / regulation of toll-like receptor 6 signaling pathway / positive regulation of complement activation, classical pathway / detection of lipoteichoic acid / regulation of macrophage inflammatory protein 1 alpha production / regulation of hippocampal neuron apoptotic process / regulation of plasma membrane bounded cell projection organization / : / positive regulation of C-C chemokine receptor CCR7 signaling pathway / excitatory synapse pruning / positive regulation of CD40 signaling pathway / negative regulation of cell activation / detection of peptidoglycan / positive regulation of macrophage fusion / import into cell / sulfatide binding / negative regulation of macrophage colony-stimulating factor signaling pathway / positive regulation of antigen processing and presentation of peptide antigen via MHC class II / negative regulation of fat cell proliferation / lipoteichoic acid binding / positive regulation of engulfment of apoptotic cell / positive regulation of establishment of protein localization / positive regulation of synapse pruning / microglial cell activation involved in immune response / regulation of intracellular signal transduction / negative regulation of toll-like receptor 2 signaling pathway / positive regulation of CAMKK-AMPK signaling cascade / negative regulation of autophagic cell death / respiratory burst after phagocytosis / positive regulation of low-density lipoprotein particle clearance / negative regulation of astrocyte activation / semaphorin receptor binding / positive regulation of microglial cell migration / apolipoprotein A-I binding / Other semaphorin interactions / detection of lipopolysaccharide / CXCL12-activated CXCR4 signaling pathway / T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell / negative regulation of toll-like receptor 4 signaling pathway / negative regulation of neuroinflammatory response / high-density lipoprotein particle binding / negative regulation of p38MAPK cascade / very-low-density lipoprotein particle binding / negative regulation of glial cell apoptotic process / cellular response to oxidised low-density lipoprotein particle stimulus / dendritic cell differentiation / complement-mediated synapse pruning / negative regulation of NLRP3 inflammasome complex assembly / microglial cell proliferation / regulation of TOR signaling / positive regulation of microglial cell activation / semaphorin receptor complex / low-density lipoprotein particle binding / phagocytosis, recognition / amyloid-beta clearance by cellular catabolic process / regulation of resting membrane potential / cellular response to lipoprotein particle stimulus / positive regulation of phagocytosis, engulfment / cellular response to peptidoglycan / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / peptidoglycan binding / positive regulation of chemotaxis / positive regulation of amyloid-beta clearance / semaphorin receptor activity / positive regulation of proteasomal protein catabolic process / positive regulation of kinase activity / phosphatidylethanolamine binding / kinase activator activity / positive regulation of osteoclast differentiation / negative regulation of amyloid fibril formation / cellular response to lipid / regulation of interleukin-6 production / apoptotic cell clearance / dendritic spine maintenance / negative regulation of triglyceride storage / negative regulation of interleukin-1 beta production / phagocytosis, engulfment / regulation of innate immune response / positive regulation of ATP biosynthetic process / phosphatidylserine binding / negative regulation of cholesterol storage / pyroptotic inflammatory response / regulation of cytokine production involved in inflammatory response / lipid homeostasis / social behavior / cellular response to lipoteichoic acid / amyloid-beta clearance / lipoprotein particle binding / humoral immune response / positive regulation of interleukin-10 production / regulation of lipid metabolic process / apolipoprotein binding / negative regulation of tumor necrosis factor production / plasma membrane raft / positive regulation of cholesterol efflux / positive regulation of TOR signaling / negative regulation of cytokine production involved in inflammatory response / response to axon injury / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phagocytosis
Similarity search - Function
: / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Triggering receptor expressed on myeloid cells 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsSzykowska, A. / Preger, C. / Williams, E. / Mukhopadhyay, S.M.M. / McKinley, G. / Gruslund, S. / Wigren, E. / Persson, H. / Arrowsmith, C.H. / Edwards, A. ...Szykowska, A. / Preger, C. / Williams, E. / Mukhopadhyay, S.M.M. / McKinley, G. / Gruslund, S. / Wigren, E. / Persson, H. / Arrowsmith, C.H. / Edwards, A. / von Delft, F. / Bountra, C. / Davis, J.B. / Di Daniel, E. / Burgess-Brown, N. / Bullock, A.
Citation
Journal: Structure / Year: 2021
Title: Selection and structural characterization of anti-TREM2 scFvs that reduce levels of shed ectodomain.
Authors: Szykowska, A. / Chen, Y. / Smith, T.B. / Preger, C. / Yang, J. / Qian, D. / Mukhopadhyay, S.M. / Wigren, E. / Neame, S.J. / Graslund, S. / Persson, H. / Atkinson, P.J. / Di Daniel, E. / ...Authors: Szykowska, A. / Chen, Y. / Smith, T.B. / Preger, C. / Yang, J. / Qian, D. / Mukhopadhyay, S.M. / Wigren, E. / Neame, S.J. / Graslund, S. / Persson, H. / Atkinson, P.J. / Di Daniel, E. / Mead, E. / Wang, J. / Davis, J.B. / Burgess-Brown, N.A. / Bullock, A.N.
#1: Journal: Biorxiv / Year: 2021
Title: Selection and structural characterisation of anti-TREM2 scFvs that reduce levels of shed ectodomain
Authors: Szykowska, A. / Chen, Y. / Smith, T.B. / Preger, C. / Yang, J. / Qian, D. / Mukhopadhyay, S. / Wigren, E. / Neame, S.J. / Graslund, S. / Persson, H. / Atkinson, P.J. / Di Daniel, E. / Mead, ...Authors: Szykowska, A. / Chen, Y. / Smith, T.B. / Preger, C. / Yang, J. / Qian, D. / Mukhopadhyay, S. / Wigren, E. / Neame, S.J. / Graslund, S. / Persson, H. / Atkinson, P.J. / Di Daniel, E. / Mead, E. / Wang, J. / Davis, J.B. / Burgess-Brown, N.A. / Bullock, A.N.
History
DepositionFeb 26, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 21, 2021Group: Database references / Category: citation / citation_author
Revision 1.2Nov 17, 2021Group: Data collection / Database references
Category: citation / database_2 ...citation / database_2 / diffrn_source / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_site
Revision 1.3Dec 21, 2022Group: Data collection / Database references / Source and taxonomy
Category: citation / diffrn_source / entity_src_gen
Item: _citation.journal_id_ISSN / _citation.page_last ..._citation.journal_id_ISSN / _citation.page_last / _diffrn_source.pdbx_synchrotron_site / _entity_src_gen.gene_src_common_name / _entity_src_gen.host_org_common_name
Revision 1.4Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Triggering receptor expressed on myeloid cells 2
B: Triggering receptor expressed on myeloid cells 2
C: Single chain variable
D: Single chain variable
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,3256
Polymers97,8824
Non-polymers4422
Water6,756375
1
A: Triggering receptor expressed on myeloid cells 2
D: Single chain variable
hetero molecules

A: Triggering receptor expressed on myeloid cells 2
D: Single chain variable
hetero molecules

B: Triggering receptor expressed on myeloid cells 2
C: Single chain variable
hetero molecules

B: Triggering receptor expressed on myeloid cells 2
C: Single chain variable
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,64912
Polymers195,7648
Non-polymers8854
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555-x,y,-z1
crystal symmetry operation3_545-y,x-1,z+1/41
crystal symmetry operation7_544y,x-1,-z-1/41
Buried area13650 Å2
ΔGint-78 kcal/mol
Surface area56140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.661, 111.661, 232.196
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number91
Space group name H-MP4122
Space group name HallP4w2c
Symmetry operation#1: x,y,z
#2: -y,x,z+1/4
#3: y,-x,z+3/4
#4: x,-y,-z+1/2
#5: -x,y,-z
#6: -x,-y,z+1/2
#7: y,x,-z+3/4
#8: -y,-x,-z+1/4

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Components

#1: Protein Triggering receptor expressed on myeloid cells 2 / TREM-2 / Triggering receptor expressed on monocytes 2


Mass: 22696.100 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: NAG - N-acetyl-D-glucosoamine attached to Asparagine 79
Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Gene: TREM2 / Variant: TREM2A / Plasmid: pHTBV1.1-NH-Sec / Details (production host): secreted / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / Variant (production host): TREM2A / References: UniProt: Q9NZC2
#2: Antibody Single chain variable


Mass: 26244.982 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pFB-NH-sec / Details (production host): secretion / Production host: Spodoptera frugiperda (fall armyworm)
#3: 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.: 2
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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 375 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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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: 4.7 Å3/Da / Density % sol: 73.85 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.2M potassium chloride, 35% pentaerythritol propoxylate 5/4, 0.1M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 8, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.26→100.63 Å / Num. obs: 69496 / % possible obs: 99.8 % / Redundancy: 21.4 % / Biso Wilson estimate: 39.46 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.2129 / Rrim(I) all: 0.218 / Net I/σ(I): 9.96
Reflection shellResolution: 2.26→2.341 Å / Num. unique obs: 6791 / CC1/2: 0.694

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Processing

Software
NameVersionClassification
PHASER1.17.1_3660phasing
PHENIX1.17.1_3660refinement
PHENIX1.17.1_3660data processing
Cootmodel building
xia2data processing
xia2data reduction
DIALSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5UD7 6G8R

5ud7

6g8r


Resolution: 2.26→100.63 Å / SU ML: 0.2771 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.8978
RfactorNum. reflection% reflection
Rfree0.216 3452 4.97 %
Rwork0.1911 --
obs0.1924 69496 99.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 42.78 Å2
Refinement stepCycle: LAST / Resolution: 2.26→100.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5382 0 14 375 5771
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00195524
X-RAY DIFFRACTIONf_angle_d0.49687493
X-RAY DIFFRACTIONf_chiral_restr0.0407815
X-RAY DIFFRACTIONf_plane_restr0.0032950
X-RAY DIFFRACTIONf_dihedral_angle_d15.17861961
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.26-2.290.33281370.30082487X-RAY DIFFRACTION95.11
2.29-2.320.3161450.29372593X-RAY DIFFRACTION99.89
2.32-2.360.28871430.28122581X-RAY DIFFRACTION99.78
2.36-2.390.32261320.28372601X-RAY DIFFRACTION99.96
2.39-2.430.32211350.2662627X-RAY DIFFRACTION99.93
2.43-2.470.3171570.2592574X-RAY DIFFRACTION99.78
2.47-2.520.3091360.26482592X-RAY DIFFRACTION99.89
2.52-2.570.29011270.24672615X-RAY DIFFRACTION99.96
2.57-2.620.32391440.2332619X-RAY DIFFRACTION99.93
2.62-2.680.27491400.22482622X-RAY DIFFRACTION99.82
2.68-2.740.28591490.22232596X-RAY DIFFRACTION99.78
2.74-2.810.25391190.21482641X-RAY DIFFRACTION99.57
2.81-2.880.23831300.2162610X-RAY DIFFRACTION99.75
2.88-2.970.26171530.18732612X-RAY DIFFRACTION99.78
2.97-3.060.21171310.18622625X-RAY DIFFRACTION99.75
3.06-3.170.21651450.17772642X-RAY DIFFRACTION99.96
3.17-3.30.20471300.17862664X-RAY DIFFRACTION99.86
3.3-3.450.17941570.17232605X-RAY DIFFRACTION99.78
3.45-3.630.17961440.1652660X-RAY DIFFRACTION99.96
3.63-3.860.17621170.16062696X-RAY DIFFRACTION99.96
3.86-4.160.15371240.16512708X-RAY DIFFRACTION100
4.16-4.580.15711500.14012655X-RAY DIFFRACTION100
4.58-5.240.1611390.14642721X-RAY DIFFRACTION100
5.24-6.60.2131470.19262766X-RAY DIFFRACTION99.86
6.6-100.630.24141210.21952932X-RAY DIFFRACTION99.35

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