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- PDB-8pvq: Crystal Structure of Human PTX3 C-terminal domain -

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Basic information

Entry
Database: PDB / ID: 8pvq
TitleCrystal Structure of Human PTX3 C-terminal domain
ComponentsPentraxin-related protein PTX3
KeywordsIMMUNE SYSTEM / Binding protein
Function / homology
Function and homology information


(1->3)-beta-D-glucan binding / negative regulation by host of viral glycoprotein metabolic process / negative regulation of glycoprotein metabolic process / ovarian cumulus expansion / host-mediated suppression of viral proces / complement component C1q complex binding / opsonization / response to yeast / host-mediated suppression of symbiont invasion / virion binding ...(1->3)-beta-D-glucan binding / negative regulation by host of viral glycoprotein metabolic process / negative regulation of glycoprotein metabolic process / ovarian cumulus expansion / host-mediated suppression of viral proces / complement component C1q complex binding / opsonization / response to yeast / host-mediated suppression of symbiont invasion / virion binding / extracellular matrix organization / positive regulation of phagocytosis / specific granule lumen / positive regulation of nitric oxide biosynthetic process / tertiary granule lumen / extracellular matrix / inflammatory response / innate immune response / Neutrophil degranulation / : / extracellular region / identical protein binding
Similarity search - Function
Pentraxin-related protein PTX3 / : / PTX3-like, N-terminal domain / LamG-like jellyroll fold / LamG-like jellyroll fold domain / Pentaxin, conserved site / Pentraxin domain signature. / Pentaxin family / Pentraxin / C-reactive protein / pentaxin family / Pentraxin-related ...Pentraxin-related protein PTX3 / : / PTX3-like, N-terminal domain / LamG-like jellyroll fold / LamG-like jellyroll fold domain / Pentaxin, conserved site / Pentraxin domain signature. / Pentaxin family / Pentraxin / C-reactive protein / pentaxin family / Pentraxin-related / Pentraxin (PTX) domain profile. / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Pentraxin-related protein PTX3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsLevy, C.W.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/T001542/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/T017643/1 United Kingdom
CitationJournal: Matrix Biol / Year: 2025
Title: The structural organisation of pentraxin-3 and its interactions with heavy chains of inter-α-inhibitor regulate crosslinking of the hyaluronan matrix.
Authors: Anokhi Shah / Xiaoli Zhang / Matthew Snee / Michael P Lockhart-Cairns / Colin W Levy / Thomas A Jowitt / Holly L Birchenough / Louisa Dean / Richard Collins / Rebecca J Dodd / Abigail R E ...Authors: Anokhi Shah / Xiaoli Zhang / Matthew Snee / Michael P Lockhart-Cairns / Colin W Levy / Thomas A Jowitt / Holly L Birchenough / Louisa Dean / Richard Collins / Rebecca J Dodd / Abigail R E Roberts / Jan J Enghild / Alberto Mantovani / Juan Fontana / Clair Baldock / Antonio Inforzato / Ralf P Richter / Anthony J Day /
Abstract: Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large ...Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large polysaccharide hyaluronan (HA) to which heavy chains (HCs) of the inter-α-inhibitor (IαI) family of proteoglycans are covalently attached, playing a key role in the (non-covalent) crosslinking of HC•HA complexes. These interactions stabilise the cumulus matrix, essential for ovulation and fertilisation in mammals, and are also implicated in the formation of pathogenic matrices in the context of viral lung infections. To better understand the physiological and pathological roles of PTX3 we have analysed how its quaternary structure underpins HA crosslinking via its interactions with HCs. A combination of X-ray crystallography, cryo-electron microscopy (cryo-EM) and AlphaFold predictive modelling revealed that the C-terminal pentraxin domains of the PTX3 octamer are arranged in a central cube, with two long extensions on either side, each formed from four protomers assembled into tetrameric coiled-coil regions, essentially as described by (Noone et al., 2022; doi:10.1073/pnas.2208144119). From crystallography and cryo-EM data, we identified a network of inter-protomer salt bridges that facilitate the assembly of the octamer. Small angle X-ray scattering (SAXS) validated our model for the octameric protein, including the analysis of two PTX3 constructs: a tetrameric 'Half-PTX3' and a construct missing the 24 N-terminal residues (Δ1-24_PTX3). SAXS determined a length of ∼520 Å for PTX3 and, combined with 3D variability analysis of cryo-EM data, defined the flexibility of the N-terminal extensions. Biophysical analyses revealed that the prototypical heavy chain HC1 does not interact with PTX3 at pH 7.4, consistent with our previous studies showing that, at this pH, PTX3 only associates with HC•HA complexes if they are formed in its presence. However, PTX3 binds to HC1 at acidic pH, and can also be incorporated into pre-formed HC•HA complexes under these conditions. This provides a novel mechanism for the regulation of PTX3-mediated HA crosslinking (e.g., during inflammation), likely mediated by a pH-dependent conformational change in HC1. The PTX3 octamer was found to associate simultaneously with up to eight HC1 molecules and, thus, has the potential to form a major crosslinking node within HC•HA matrices, i.e., where the physical and biochemical properties of resulting matrices could be tuned by the HC/PTX3 composition.
History
DepositionJul 18, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature
Revision 1.2Feb 4, 2026Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Pentraxin-related protein PTX3


Theoretical massNumber of molelcules
Total (without water)22,6111
Polymers22,6111
Non-polymers00
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area8890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)138.003, 138.003, 69.550
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32
Space group name HallR32"
Symmetry operation#1: x,y,z
#2: -y,x-y,z
#3: -x+y,-x,z
#4: x-y,-y,-z
#5: -x,-x+y,-z
#6: y,x,-z
#7: x+1/3,y+2/3,z+2/3
#8: -y+1/3,x-y+2/3,z+2/3
#9: -x+y+1/3,-x+2/3,z+2/3
#10: x-y+1/3,-y+2/3,-z+2/3
#11: -x+1/3,-x+y+2/3,-z+2/3
#12: y+1/3,x+2/3,-z+2/3
#13: x+2/3,y+1/3,z+1/3
#14: -y+2/3,x-y+1/3,z+1/3
#15: -x+y+2/3,-x+1/3,z+1/3
#16: x-y+2/3,-y+1/3,-z+1/3
#17: -x+2/3,-x+y+1/3,-z+1/3
#18: y+2/3,x+1/3,-z+1/3

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Components

#1: Protein Pentraxin-related protein PTX3 / Pentaxin-related protein PTX3 / Tumor necrosis factor alpha-induced protein 5 / TNF alpha-induced ...Pentaxin-related protein PTX3 / Tumor necrosis factor alpha-induced protein 5 / TNF alpha-induced protein 5 / Tumor necrosis factor-inducible gene 14 protein / TSG-14


Mass: 22610.596 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTX3, TNFAIP5, TSG14 / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P26022
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O
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: 2.82 Å3/Da / Density % sol: 56.36 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 10% w/v PEG 8000, 20% v/v ethylene glycol, 0.03 M of each halide, 0.1 M MOPS/HEPES-Na pH 7.5) * 0.3 M sodium fluoride, 0.3 M sodium bromide, 0.3 M sodium iodide
Temp details: Cold room

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: May 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 2.43→45.33 Å / Num. obs: 9663 / % possible obs: 99.54 % / Redundancy: 6.5 % / Biso Wilson estimate: 62.77 Å2 / CC1/2: 0.998 / Rpim(I) all: 0.044 / Net I/σ(I): 8.66
Reflection shellResolution: 2.43→2.517 Å / Mean I/σ(I) obs: 1.08 / Num. unique obs: 950 / CC1/2: 0.892 / Rpim(I) all: 0.66 / % possible all: 99.37

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
xia2data reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.43→45.33 Å / SU ML: 0.307 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 36.8652
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2623 483 5.01 %
Rwork0.2164 9154 -
obs0.2187 9637 99.49 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 69.94 Å2
Refinement stepCycle: LAST / Resolution: 2.43→45.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1546 0 0 21 1567
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00881580
X-RAY DIFFRACTIONf_angle_d0.78982142
X-RAY DIFFRACTIONf_chiral_restr0.0546237
X-RAY DIFFRACTIONf_plane_restr0.005274
X-RAY DIFFRACTIONf_dihedral_angle_d5.516212
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.43-2.780.37271590.30453009X-RAY DIFFRACTION99.28
2.78-3.50.33011610.25453035X-RAY DIFFRACTION99.72
3.5-45.330.22471630.1913110X-RAY DIFFRACTION99.48

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