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- PDB-7o7p: (h-alpha2M)4 activated state -

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Basic information

Entry
Database: PDB / ID: 7o7p
Title(h-alpha2M)4 activated state
ComponentsAlpha-2-macroglobulin
KeywordsPROTEIN BINDING / alpha2-macroglobulin / proteinase / serum proteostasis / hydrolase inhibitor
Function / homology
Function and homology information


negative regulation of complement activation, lectin pathway / interleukin-1 binding / brain-derived neurotrophic factor binding / embryonic liver development / acute inflammatory response to antigenic stimulus / interleukin-8 binding / luteinization / tumor necrosis factor binding / HDL assembly / response to carbon dioxide ...negative regulation of complement activation, lectin pathway / interleukin-1 binding / brain-derived neurotrophic factor binding / embryonic liver development / acute inflammatory response to antigenic stimulus / interleukin-8 binding / luteinization / tumor necrosis factor binding / HDL assembly / response to carbon dioxide / nerve growth factor binding / endopeptidase inhibitor activity / growth factor binding / response to prostaglandin E / response to glucocorticoid / Intrinsic Pathway of Fibrin Clot Formation / Degradation of the extracellular matrix / response to nutrient / negative regulation of peptidase activity / platelet alpha granule lumen / acute-phase response / stem cell differentiation / serine-type endopeptidase inhibitor activity / calcium-dependent protein binding / Platelet degranulation / protease binding / collagen-containing extracellular matrix / blood microparticle / signaling receptor binding / enzyme binding / extracellular space / extracellular exosome / extracellular region / identical protein binding
Similarity search - Function
Alpha-2-macroglobulin, TED domain / TonB box, conserved site / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Macroglobulin domain MG4 / Macroglobulin domain MG4 / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily ...Alpha-2-macroglobulin, TED domain / TonB box, conserved site / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Macroglobulin domain MG4 / Macroglobulin domain MG4 / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG3 / A-macroglobulin receptor / Alpha-2-macroglobulin / Macroglobulin domain / Alpha-2-macroglobulin, bait region domain / Alpha-macroglobulin-like, TED domain / Alpha-2-macroglobulin family / MG2 domain / A-macroglobulin TED domain / Alpha-2-macroglobulin bait region domain / Alpha-2-Macroglobulin / Alpha-2-macroglobulin family / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Immunoglobulin E-set / Immunoglobulin-like fold
Similarity search - Domain/homology
Alpha-2-macroglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.6 Å
AuthorsLuque, D. / Goulas, T. / Mata, C.P. / Mendes, S.R. / Gomis-Ruth, F.X. / Caston, J.R.
Funding support Spain, 4items
OrganizationGrant numberCountry
Spanish Ministry of Economy and CompetitivenessBFU2017-88736-R Spain
Spanish Ministry of Economy and CompetitivenessBFU2019-107725-RB-I00 Spain
Spanish Ministry of Economy and CompetitivenessJCI-2012-13573 Spain
Spanish Ministry of Science, Innovation, and UniversitiesBES2016-076877 Spain
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α-macroglobulin.
Authors: Daniel Luque / Theodoros Goulas / Carlos P Mata / Soraia R Mendes / F Xavier Gomis-Rüth / José R Castón /
Abstract: Human α2-macroglobulin (hα2M) is a multidomain protein with a plethora of essential functions, including transport of signaling molecules and endopeptidase inhibition in innate immunity. Here, we ...Human α2-macroglobulin (hα2M) is a multidomain protein with a plethora of essential functions, including transport of signaling molecules and endopeptidase inhibition in innate immunity. Here, we dissected the molecular mechanism of the inhibitory function of the ∼720-kDa hα2M tetramer through eight cryo–electron microscopy (cryo-EM) structures of complexes from human plasma. In the native complex, the hα2M subunits are organized in two flexible modules in expanded conformation, which enclose a highly porous cavity in which the proteolytic activity of circulating plasma proteins is tested. Cleavage of bait regions exposed inside the cavity triggers rearrangement to a compact conformation, which closes openings and entraps the prey proteinase. After the expanded-to-compact transition, which occurs independently in the four subunits, the reactive thioester bond triggers covalent linking of the proteinase, and the receptor-binding domain is exposed on the tetramer surface for receptor-mediated clearance from circulation. These results depict the molecular mechanism of a unique suicidal inhibitory trap.
History
DepositionApr 13, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 13, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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
Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _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: Alpha-2-macroglobulin
B: Alpha-2-macroglobulin
C: Alpha-2-macroglobulin
D: Alpha-2-macroglobulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)661,68032
Polymers653,8604
Non-polymers7,81928
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area24970 Å2
ΔGint15 kcal/mol
Surface area236330 Å2
MethodPISA

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Components

#1: Protein
Alpha-2-macroglobulin / Alpha-2-M / C3 and PZP-like alpha-2-macroglobulin domain-containing protein 5


Mass: 163465.062 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P01023
#2: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#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.: 20 / 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
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human alpha-2-macroglobulin activated state / Type: COMPLEX / Entity ID: #1 / Source: NATURAL
Molecular weightValue: 0.7 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human) / Organ: Blood plasma
Buffer solutionpH: 7.5
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER/RHODIUM / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: LEICA EM CPC / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 47775 X / Nominal defocus max: 3250 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 39.6 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 12143
Image scansMovie frames/image: 32

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Processing

EM software
IDNameVersionCategory
1RELION2.1particle selection
2EPUimage acquisition
4CTFFIND4.1CTF correction
7Coot0.9model fitting
9PHENIX1.15model refinement
10RELION2.1initial Euler assignment
11RELION2.1final Euler assignment
12RELION2.1classification
13RELION2.13D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1625000
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118333 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL

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