+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-12754 | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Title | (h-alpha2M)4 plasmin-activated I state | |||||||||||||||
Map data | (h-alpha2M)4 plasmin-activated I state | |||||||||||||||
Sample |
| |||||||||||||||
Function / homology | Function and homology information negative regulation of complement activation, lectin pathway / interleukin-1 binding / brain-derived neurotrophic factor binding / interleukin-8 binding / response to prostaglandin E / embryonic liver development / acute inflammatory response to antigenic stimulus / luteinization / tumor necrosis factor binding / HDL assembly ...negative regulation of complement activation, lectin pathway / interleukin-1 binding / brain-derived neurotrophic factor binding / interleukin-8 binding / response to prostaglandin E / embryonic liver development / acute inflammatory response to antigenic stimulus / luteinization / tumor necrosis factor binding / HDL assembly / response to carbon dioxide / nerve growth factor binding / endopeptidase inhibitor activity / growth factor binding / response to glucocorticoid / Intrinsic Pathway of Fibrin Clot Formation / Degradation of the extracellular matrix / response to nutrient / platelet alpha granule lumen / acute-phase response / stem cell differentiation / serine-type endopeptidase inhibitor activity / calcium-dependent protein binding / Platelet degranulation / collagen-containing extracellular matrix / protease binding / blood microparticle / signaling receptor binding / enzyme binding / extracellular space / extracellular exosome / extracellular region / identical protein binding Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) / Human (human) | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.9 Å | |||||||||||||||
Authors | Luque D / Goulas T / Mata CP / Mendes SR / Gomis-Ruth FX / Caston JR | |||||||||||||||
Funding support | Spain, 4 items
| |||||||||||||||
Citation | Journal: 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 |
|
-Structure visualization
Supplemental images |
---|
-Downloads & links
-EMDB archive
Map data | emd_12754.map.gz | 93.5 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-12754-v30.xml emd-12754.xml | 14.6 KB 14.6 KB | Display Display | EMDB header |
Images | emd_12754.png | 127.9 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-12754 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-12754 | HTTPS FTP |
-Validation report
Summary document | emd_12754_validation.pdf.gz | 396.5 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_12754_full_validation.pdf.gz | 396.1 KB | Display | |
Data in XML | emd_12754_validation.xml.gz | 6.6 KB | Display | |
Data in CIF | emd_12754_validation.cif.gz | 7.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-12754 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-12754 | HTTPS FTP |
-Related structure data
Related structure data | 7o7rMC 7o7lC 7o7mC 7o7nC 7o7oC 7o7pC 7o7qC 7o7sC M: atomic model generated by this map C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|---|
Related items in Molecule of the Month |
-Map
File | Download / File: emd_12754.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | (h-alpha2M)4 plasmin-activated I state | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.052 Å | ||||||||||||||||||||
Density |
| ||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Sample components
-Entire : Human alpha-2-macroglobulin plasmin-activated I state
Entire | Name: Human alpha-2-macroglobulin plasmin-activated I state |
---|---|
Components |
|
-Supramolecule #1: Human alpha-2-macroglobulin plasmin-activated I state
Supramolecule | Name: Human alpha-2-macroglobulin plasmin-activated I state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
---|---|
Source (natural) | Organism: Homo sapiens (human) / Organ: Blood plasma |
Molecular weight | Theoretical: 700 KDa |
-Macromolecule #1: Alpha-2-macroglobulin
Macromolecule | Name: Alpha-2-macroglobulin / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: Human (human) |
Molecular weight | Theoretical: 163.465062 KDa |
Sequence | String: MGKNKLLHPS LVLLLLVLLP TDASVSGKPQ YMVLVPSLLH TETTEKGCVL LSYLNETVTV SASLESVRGN RSLFTDLEAE NDVLHCVAF AVPKSSSNEE VMFLTVQVKG PTQEFKKRTT VMVKNEDSLV FVQTDKSIYK PGQTVKFRVV SMDENFHPLN E LIPLVYIQ ...String: MGKNKLLHPS LVLLLLVLLP TDASVSGKPQ YMVLVPSLLH TETTEKGCVL LSYLNETVTV SASLESVRGN RSLFTDLEAE NDVLHCVAF AVPKSSSNEE VMFLTVQVKG PTQEFKKRTT VMVKNEDSLV FVQTDKSIYK PGQTVKFRVV SMDENFHPLN E LIPLVYIQ DPKGNRIAQW QSFQLEGGLK QFSFPLSSEP FQGSYKVVVQ KKSGGRTEHP FTVEEFVLPK FEVQVTVPKI IT ILEEEMN VSVCGLYTYG KPVPGHVTVS ICRKYSDASD CHGEDSQAFC EKFSGQLNSH GCFYQQVKTK VFQLKRKEYE MKL HTEAQI QEEGTVVELT GRQSSEITRT ITKLSFVKVD SHFRQGIPFF GQVRLVDGKG VPIPNKVIFI RGNEANYYSN ATTD EHGLV QFSINTTNVM GTSLTVRVNY KDRSPCYGYQ WVSEEHEEAH HTAYLVFSPS KSFVHLEPMS HELPCGHTQT VQAHY ILNG GTLLGLKKLS FYYLIMAKGG IVRTGTHGLL VKQEDMKGHF SISIPVKSDI APVARLLIYA VLPTGDVIGD SAKYDV ENC LANKVDLSFS PSQSLPASHA HLRVTAAPQS VCALRAVDQS VLLMKPDAEL SASSVYNLLP EKDLTGFPGP LNDQDNE DC INRHNVYING ITYTPVSSTN EKDMYSFLED MGLKAFTNSK IRKPKMCPQL QQYEMHGPEG LRVGFYESDV MGRGHARL V HVEEPHTETV RKYFPETWIW DLVVVNSAGV AEVGVTVPDT ITEWKAGAFC LSEDAGLGIS STASLRAFQP FFVELTMPY SVIRGEAFTL KATVLNYLPK CIRVSVQLEA SPAFLAVPVE KEQAPHCICA NGRQTVSWAV TPKSLGNVNF TVSAEALESQ ELCGTEVPS VPEHGRKDTV IKPLLVEPEG LEKETTFNSL LCPSGGEVSE ELSLKLPPNV VEESARASVS VLGDILGSAM Q NTQNLLQM PYGCGEQNMV LFAPNIYVLD YLNETQQLTP EIKSKAIGYL NTGYQRQLNY KHYDGSYSTF GERYGRNQGN TW LTAFVLK TFAQARAYIF IDEAHITQAL IWLSQRQKDN GCFRSSGSLL NNAIKGGVED EVTLSAYITI ALLEIPLTVT HPV VRNALF CLESAWKTAQ EGDHGSHVYT KALLAYAFAL AGNQDKRKEV LKSLNEEAVK KDNSVHWERP QKPKAPVGHF YEPQ APSAE VEMTSYVLLA YLTAQPAPTS EDLTSATNIV KWITKQQNAQ GGFSSTQDTV VALHALSKYG AATFTRTGKA AQVTI QSSG TFSSKFQVDN NNRLLLQQVS LPELPGEYSM KVTGEGCVYL QTSLKYNILP EKEEFPFALG VQTLPQTCDE PKAHTS FQI SLSVSYTGSR SASNMAIVDV KMVSGFIPLK PTVKMLERSN HVSRTEVSSN HVLIYLDKVS NQTLSLFFTV LQDVPVR DL KPAIVKVYDY YETDEFAIAE YNAPCSKDLG NA |
-Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 20 / Formula: NAG |
---|---|
Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.1 mg/mL |
---|---|
Buffer | pH: 7.5 |
Grid | Model: Quantifoil R2/2 / Material: COPPER/RHODIUM / Mesh: 300 |
Vitrification | Cryogen name: ETHANE / Instrument: LEICA EM CPC |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 4978 / Average electron dose: 38.7 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.7 µm / Nominal defocus min: 1.3 µm / Nominal magnification: 130000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: OTHER |
---|---|
Output model | PDB-7o7r: |