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- PDB-8b7d: Luminal domain of TMEM106B -

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Basic information

Entry
Database: PDB / ID: 8b7d
TitleLuminal domain of TMEM106B
ComponentsTransmembrane protein 106B
KeywordsMEMBRANE PROTEIN / luminal domain / fibronectin type III (Fn3) / 7-bladed beta-sandwich fold / receptor binding / SARS CoV2 / Covid19
Function / homology
Function and homology information


lysosomal protein catabolic process / regulation of lysosome organization / lysosomal lumen acidification / lysosome localization / lysosomal transport / positive regulation of dendrite development / dendrite morphogenesis / lysosome organization / neuron cellular homeostasis / late endosome membrane ...lysosomal protein catabolic process / regulation of lysosome organization / lysosomal lumen acidification / lysosome localization / lysosomal transport / positive regulation of dendrite development / dendrite morphogenesis / lysosome organization / neuron cellular homeostasis / late endosome membrane / ATPase binding / lysosome / endosome / lysosomal membrane / plasma membrane
Similarity search - Function
Transmembrane protein 106 / : / : / TM106 protein C-terminal domain / Transmembrane protein 106 N-terminal region
Similarity search - Domain/homology
Transmembrane protein 106B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 Å
AuthorsPye, V.E. / Roustan, C. / Cherepanov, P.
Funding support United Kingdom, 4items
OrganizationGrant numberCountry
Cancer Research UKFC001061 United Kingdom
Wellcome TrustFC001061 United Kingdom
Medical Research Council (MRC, United Kingdom)FC001061 United Kingdom
The Francis Crick InstituteFC001061 United Kingdom
CitationJournal: Cell / Year: 2023
Title: TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry.
Authors: Jim Baggen / Maarten Jacquemyn / Leentje Persoons / Els Vanstreels / Valerie E Pye / Antoni G Wrobel / Valeria Calvaresi / Stephen R Martin / Chloë Roustan / Nora B Cronin / Eamonn Reading ...Authors: Jim Baggen / Maarten Jacquemyn / Leentje Persoons / Els Vanstreels / Valerie E Pye / Antoni G Wrobel / Valeria Calvaresi / Stephen R Martin / Chloë Roustan / Nora B Cronin / Eamonn Reading / Hendrik Jan Thibaut / Thomas Vercruysse / Piet Maes / Frederik De Smet / Angie Yee / Toey Nivitchanyong / Marina Roell / Natalia Franco-Hernandez / Herve Rhinn / Alusha Andre Mamchak / Maxime Ah Young-Chapon / Eric Brown / Peter Cherepanov / Dirk Daelemans /
Abstract: SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane ...SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B.
History
DepositionSep 29, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 19, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 16, 2023Group: Data collection / Database references / Category: citation / diffrn_source
Item: _citation.journal_volume / _citation.page_first / _diffrn_source.pdbx_synchrotron_site
Revision 1.2May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Transmembrane protein 106B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,6585
Polymers22,7731
Non-polymers8854
Water905
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1120 Å2
ΔGint15 kcal/mol
Surface area8860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.408, 52.408, 132.922
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

#1: Protein Transmembrane protein 106B


Mass: 22772.691 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMEM106B / Cell line (production host): HEK293T / Production host: Homo sapiens (human) / References: UniProt: Q9NUM4
#2: 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.: 4 / Source method: obtained synthetically / 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
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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 Å3/Da / Density % sol: 38.62 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 2.0 M NaCl, 0.1 M BisTris-HCl, pH 5.5 / PH range: 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X CdTe 9M / Detector: PIXEL / Date: Aug 7, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.59→48.76 Å / Num. obs: 6291 / % possible obs: 100 % / Redundancy: 25 % / Biso Wilson estimate: 74.79 Å2 / CC1/2: 0.371 / Rmerge(I) obs: 0.187 / Rpim(I) all: 0.038 / Net I/σ(I): 13.5
Reflection shellResolution: 2.59→2.64 Å / Redundancy: 25.8 % / Rmerge(I) obs: 3.804 / Num. unique obs: 301 / CC1/2: 0.371 / Rpim(I) all: 0.756 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIXdev_4682refinement
DIALSdata reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: alpha fold model Q8N353

Resolution: 2.59→48.76 Å / SU ML: 0.3241 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21.6547
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2426 299 4.79 %
Rwork0.2343 5943 -
obs0.2349 6242 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 75.38 Å2
Refinement stepCycle: LAST / Resolution: 2.59→48.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1185 0 56 5 1246
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00451261
X-RAY DIFFRACTIONf_angle_d0.60551715
X-RAY DIFFRACTIONf_chiral_restr0.0526216
X-RAY DIFFRACTIONf_plane_restr0.0033209
X-RAY DIFFRACTIONf_dihedral_angle_d12.4018466
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.59-3.260.32851370.31212891X-RAY DIFFRACTION99.9
3.26-48.760.22511620.21623052X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -17.5384531045 Å / Origin y: 6.48155424368 Å / Origin z: -4.4200548864 Å
111213212223313233
T0.575562771048 Å2-0.0139282744456 Å20.0104122882406 Å2-0.697095793288 Å20.0821081993109 Å2--0.595369826096 Å2
L1.01425607319 °2-1.04177167872 °20.771160543151 °2-0.780360192034 °2-0.587584691393 °2---0.211543397768 °2
S-0.00680088915369 Å °-0.144020289761 Å °-0.0573306443389 Å °0.00661555826881 Å °0.159733958337 Å °0.115529932408 Å °0.00468664007101 Å °-0.0888177163305 Å °-3.55178794179E-5 Å °
Refinement TLS groupSelection details: all

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