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- PDB-7q1y: X-ray structure of human A2ML1 -

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Basic information

Entry
Database: PDB / ID: 7q1y
TitleX-ray structure of human A2ML1
ComponentsAlpha-2-macroglobulin-like protein 1
KeywordsIMMUNE SYSTEM / protease inhibitor / thioester protein / A2M family
Function / homology
Function and homology information


peptidase inhibitor activity / regulation of endopeptidase activity / serine-type endopeptidase inhibitor activity / extracellular space / extracellular exosome
Similarity search - Function
Alpha-2-macroglobulin, TED domain / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor binding domain ...Alpha-2-macroglobulin, TED domain / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / : / Alpha-macro-globulin thiol-ester bond-forming region / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor binding domain / Macroglobulin domain MG4 / 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-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 4.4 Å
AuthorsAndersen, G.R. / Zarantonello, A. / Enghild, J.J. / Nielsen, N.S.
Funding support Denmark, 1items
OrganizationGrant numberCountry
LundbeckfondenR155-2015-2666 Denmark
CitationJournal: Nat Commun / Year: 2022
Title: Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.
Authors: Nadia Sukusu Nielsen / Alessandra Zarantonello / Seandean Lykke Harwood / Kathrine Tejlgård Jensen / Katarzyna Kjøge / Ida B Thøgersen / Leif Schauser / Jesper Lykkegaard Karlsen / ...Authors: Nadia Sukusu Nielsen / Alessandra Zarantonello / Seandean Lykke Harwood / Kathrine Tejlgård Jensen / Katarzyna Kjøge / Ida B Thøgersen / Leif Schauser / Jesper Lykkegaard Karlsen / Gregers R Andersen / Jan J Enghild /
Abstract: A2ML1 is a monomeric protease inhibitor belonging to the A2M superfamily of protease inhibitors and complement factors. Here, we investigate the protease-inhibitory mechanism of human A2ML1 and ...A2ML1 is a monomeric protease inhibitor belonging to the A2M superfamily of protease inhibitors and complement factors. Here, we investigate the protease-inhibitory mechanism of human A2ML1 and determine the structures of its native and protease-cleaved conformations. The functional inhibitory unit of A2ML1 is a monomer that depends on covalent binding of the protease (mediated by A2ML1's thioester) to achieve inhibition. In contrast to the A2M tetramer which traps proteases in two internal chambers formed by four subunits, in protease-cleaved monomeric A2ML1 disordered regions surround the trapped protease and may prevent substrate access. In native A2ML1, the bait region is threaded through a hydrophobic channel, suggesting that disruption of this arrangement by bait region cleavage triggers the extensive conformational changes that result in protease inhibition. Structural comparisons with complement C3/C4 suggest that the A2M superfamily of proteins share this mechanism for the triggering of conformational change occurring upon proteolytic activation.
History
DepositionOct 22, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 2, 2022Group: 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 1.2May 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

Downloads & links

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Assembly

Deposited unit
A: Alpha-2-macroglobulin-like protein 1
B: Alpha-2-macroglobulin-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)323,34513
Polymers318,6792
Non-polymers4,66611
Water00
1
A: Alpha-2-macroglobulin-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)162,1287
Polymers159,3391
Non-polymers2,7896
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Alpha-2-macroglobulin-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)161,2176
Polymers159,3391
Non-polymers1,8785
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)320.150, 320.150, 321.940
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
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 20 through 1454 or resid 1455...
d_2ens_1(chain "B" and (resid 20 through 1454 or resid 1455...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1LEUGLUA1 - 1374
d_12ens_1NAGNAGC
d_13ens_1NAGNAGC
d_14ens_1NAGNAGD
d_15ens_1NAGNAGD
d_16ens_1NAGNAGE
d_21ens_1LEUGLUB1 - 1374
d_22ens_1NAGNAGG
d_23ens_1NAGNAGG
d_24ens_1NAGNAGH
d_25ens_1NAGNAGH
d_26ens_1NAGNAGI

NCS oper: (Code: givenMatrix: (0.481093916746, 0.87651557369, 0.0164040345329), (-0.875117217623, 0.481271091388, -0.050477638751), (-0.0521392240911, 0.00992903187662, 0.998590464423)Vector: 53. ...NCS oper: (Code: given
Matrix: (0.481093916746, 0.87651557369, 0.0164040345329), (-0.875117217623, 0.481271091388, -0.050477638751), (-0.0521392240911, 0.00992903187662, 0.998590464423)
Vector: 53.8693994422, -96.0146051904, 53.0019772841)

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Components

#1: Protein Alpha-2-macroglobulin-like protein 1 / C3 and PZP-like alpha-2-macroglobulin domain-containing protein 9


Mass: 159339.281 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: A2ML1, CPAMD9 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: A8K2U0
#2: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#3: 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.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: 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
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: 4.92 Å3/Da / Density % sol: 75.01 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Potassium phosphate dibasic, 10 % PEG 3350 pH 9.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.9793 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 30, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 4.276→211 Å / Num. obs: 43680 / % possible obs: 99.4 % / Redundancy: 58.7 % / Biso Wilson estimate: 291.89 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.301 / Net I/σ(I): 8.75
Reflection shellResolution: 4.276→4.38 Å / Num. unique obs: 2976 / CC1/2: 0.261 / % possible all: 93.3

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: densities from EM map

Resolution: 4.4→49.37 Å / SU ML: 0.8564 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 34.4333
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2764 1846 4.6 %
Rwork0.238 38317 -
obs0.2397 40163 99.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 342.83 Å2
Refinement stepCycle: LAST / Resolution: 4.4→49.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms21458 0 307 0 21765
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006622257
X-RAY DIFFRACTIONf_angle_d0.880930261
X-RAY DIFFRACTIONf_chiral_restr0.05123505
X-RAY DIFFRACTIONf_plane_restr0.00743856
X-RAY DIFFRACTIONf_dihedral_angle_d13.06078180
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 3.29253181221 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
4.4-4.520.51491410.45152916X-RAY DIFFRACTION99.61
4.52-4.650.43261400.4012924X-RAY DIFFRACTION99.38
4.65-4.80.37111400.34962894X-RAY DIFFRACTION99.74
4.8-4.970.3621410.31962956X-RAY DIFFRACTION99.77
4.97-5.170.34941410.312899X-RAY DIFFRACTION99.97
5.17-5.410.35851410.30312931X-RAY DIFFRACTION99.93
5.41-5.690.29181420.27222941X-RAY DIFFRACTION99.81
5.69-6.050.27431410.26162942X-RAY DIFFRACTION100
6.05-6.510.28491420.24392956X-RAY DIFFRACTION100
6.51-7.170.24891420.23632946X-RAY DIFFRACTION99.97
7.17-8.20.26711440.23562978X-RAY DIFFRACTION99.97
8.2-10.320.261430.19252981X-RAY DIFFRACTION99.94
10.32-49.370.24681480.21523053X-RAY DIFFRACTION99.56
Refinement TLS params.Method: refined / Origin x: -16.9677129522 Å / Origin y: -128.11154011 Å / Origin z: 8.14432767071 Å
111213212223313233
T3.48075747143 Å2-0.0577930593949 Å20.00466986493858 Å2-3.15617487073 Å2-0.0311870315197 Å2--3.07734584623 Å2
L0.989493662313 °20.360799278825 °2-0.406039912325 °2-0.413518290021 °2-0.20166522035 °2--0.139874205197 °2
S0.0855408444035 Å °-0.19394686712 Å °0.0471306937201 Å °0.1638342886 Å °-0.176081754573 Å °-0.150252416193 Å °-0.205735653827 Å °0.102892619371 Å °-7.90949007151E-6 Å °
Refinement TLS groupSelection details: all

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