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Yorodumi- EMDB-21044: Cryo-EM structure of the integrin AlphaIIbBeta3-Abciximab complex -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-21044 | ||||||||||||
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Title | Cryo-EM structure of the integrin AlphaIIbBeta3-Abciximab complex | ||||||||||||
Map data | integrin AlphaIIbBeta3-Abciximab complex | ||||||||||||
Sample |
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Function / homology | Function and homology information tube development / regulation of serotonin uptake / positive regulation of adenylate cyclase-inhibiting opioid receptor signaling pathway / alpha9-beta1 integrin-ADAM8 complex / regulation of trophoblast cell migration / integrin alphaIIb-beta3 complex / regulation of postsynaptic neurotransmitter receptor diffusion trapping / alphav-beta3 integrin-vitronectin complex / regulation of extracellular matrix organization / platelet alpha granule membrane ...tube development / regulation of serotonin uptake / positive regulation of adenylate cyclase-inhibiting opioid receptor signaling pathway / alpha9-beta1 integrin-ADAM8 complex / regulation of trophoblast cell migration / integrin alphaIIb-beta3 complex / regulation of postsynaptic neurotransmitter receptor diffusion trapping / alphav-beta3 integrin-vitronectin complex / regulation of extracellular matrix organization / platelet alpha granule membrane / positive regulation of glomerular mesangial cell proliferation / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / alphav-beta3 integrin-PKCalpha complex / fibrinogen binding / maintenance of postsynaptic specialization structure / alphav-beta3 integrin-HMGB1 complex / blood coagulation, fibrin clot formation / vascular endothelial growth factor receptor 2 binding / negative regulation of lipid transport / glycinergic synapse / negative regulation of low-density lipoprotein receptor activity / angiogenesis involved in wound healing / Elastic fibre formation / regulation of release of sequestered calcium ion into cytosol / mesodermal cell differentiation / cell-substrate junction assembly / alphav-beta3 integrin-IGF-1-IGF1R complex / platelet-derived growth factor receptor binding / filopodium membrane / extracellular matrix binding / positive regulation of fibroblast migration / regulation of postsynaptic neurotransmitter receptor internalization / positive regulation of vascular endothelial growth factor receptor signaling pathway / apolipoprotein A-I-mediated signaling pathway / regulation of bone resorption / apoptotic cell clearance / positive regulation of cell adhesion mediated by integrin / wound healing, spreading of epidermal cells / heterotypic cell-cell adhesion / integrin complex / Molecules associated with elastic fibres / positive regulation of leukocyte migration / cellular response to insulin-like growth factor stimulus / positive regulation of cell-matrix adhesion / smooth muscle cell migration / cell adhesion mediated by integrin / microvillus membrane / negative chemotaxis / Syndecan interactions / p130Cas linkage to MAPK signaling for integrins / cellular response to platelet-derived growth factor stimulus / activation of protein kinase activity / cell-substrate adhesion / protein disulfide isomerase activity / positive regulation of smooth muscle cell migration / positive regulation of osteoblast proliferation / TGF-beta receptor signaling activates SMADs / PECAM1 interactions / lamellipodium membrane / GRB2:SOS provides linkage to MAPK signaling for Integrins / platelet-derived growth factor receptor signaling pathway / fibronectin binding / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / ECM proteoglycans / positive regulation of T cell migration / positive regulation of bone resorption / Integrin cell surface interactions / coreceptor activity / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / cell adhesion molecule binding / positive regulation of endothelial cell proliferation / embryo implantation / positive regulation of endothelial cell migration / Integrin signaling / substrate adhesion-dependent cell spreading / cell-matrix adhesion / response to activity / Signal transduction by L1 / integrin-mediated signaling pathway / regulation of actin cytoskeleton organization / protein kinase C binding / positive regulation of smooth muscle cell proliferation / wound healing / Signaling by high-kinase activity BRAF mutants / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / MAP2K and MAPK activation / platelet activation / cell-cell adhesion / platelet aggregation / VEGFA-VEGFR2 Pathway / ruffle membrane / cellular response to mechanical stimulus / positive regulation of angiogenesis / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) / synthetic construct (others) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.8 Å | ||||||||||||
Authors | Nesic D / Zhang Y / Spasic A / Li J / Provasi D / Filizola M / Walz T / Coller BS | ||||||||||||
Funding support | United States, 3 items
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Citation | Journal: Arterioscler Thromb Vasc Biol / Year: 2020 Title: Cryo-Electron Microscopy Structure of the αIIbβ3-Abciximab Complex. Authors: Dragana Nešić / Yixiao Zhang / Aleksandar Spasic / Jihong Li / Davide Provasi / Marta Filizola / Thomas Walz / Barry S Coller Abstract: OBJECTIVE: The αIIbβ3 antagonist antiplatelet drug abciximab is the chimeric antigen-binding fragment comprising the variable regions of murine monoclonal antibody 7E3 and the constant domains of ...OBJECTIVE: The αIIbβ3 antagonist antiplatelet drug abciximab is the chimeric antigen-binding fragment comprising the variable regions of murine monoclonal antibody 7E3 and the constant domains of human IgG1 and light chain κ. Previous mutagenesis studies suggested that abciximab binds to the β3 C177-C184 specificity-determining loop (SDL) and Trp129 on the adjacent β1-α1 helix. These studies could not, however, assess whether 7E3 or abciximab prevents fibrinogen binding by steric interference, disruption of either the αIIbβ3-binding pocket for fibrinogen or the β3 SDL (which is not part of the binding pocket but affects fibrinogen binding), or some combination of these effects. To address this gap, we used cryo-electron microscopy to determine the structure of the αIIbβ3-abciximab complex at 2.8 Å resolution. Approach and Results: The interacting surface of abciximab is comprised of residues from all 3 complementarity-determining regions of both the light and heavy chains, with high representation of aromatic residues. Binding is primarily to the β3 SDL and neighboring residues, the β1-α1 helix, and β3 residues Ser211, Val212 and Met335. Unexpectedly, the structure also indicated several interactions with αIIb. As judged by the cryo-electron microscopy model, molecular-dynamics simulations, and mutagenesis, the binding of abciximab does not appear to rely on the interaction with the αIIb residues and does not result in disruption of the fibrinogen-binding pocket; it does, however, compress and reduce the flexibility of the SDL. CONCLUSIONS: We deduce that abciximab prevents ligand binding by steric interference, with a potential contribution via displacement of the SDL and limitation of the flexibility of the SDL residues. | ||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_21044.map.gz | 57.5 MB | EMDB map data format | |
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Header (meta data) | emd-21044-v30.xml emd-21044.xml | 15.3 KB 15.3 KB | Display Display | EMDB header |
Images | emd_21044.png | 137.7 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-21044 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-21044 | HTTPS FTP |
-Related structure data
Related structure data | 6v4pMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_21044.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | integrin AlphaIIbBeta3-Abciximab complex | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : Integrin AlphaIIbBeta3-Abciximab Complex
Entire | Name: Integrin AlphaIIbBeta3-Abciximab Complex |
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Components |
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-Supramolecule #1: Integrin AlphaIIbBeta3-Abciximab Complex
Supramolecule | Name: Integrin AlphaIIbBeta3-Abciximab Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Macromolecule #1: Integrin alpha-IIb
Macromolecule | Name: Integrin alpha-IIb / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 104.894438 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MARALCPLQA LWLLEWVLLL LGPCAAPPAW ALNLDPVQLT FYAGPNGSQF GFSLDFHKDS HGRVAIVVGA PRTLGPSQEE TGGVFLCPW RAEGGQCPSL LFDLRDETRN VGSQTLQTFK ARQGLGASVV SWSDVIVACA PWQHWNVLEK TEEAEKTPVG S CFLAQPES ...String: MARALCPLQA LWLLEWVLLL LGPCAAPPAW ALNLDPVQLT FYAGPNGSQF GFSLDFHKDS HGRVAIVVGA PRTLGPSQEE TGGVFLCPW RAEGGQCPSL LFDLRDETRN VGSQTLQTFK ARQGLGASVV SWSDVIVACA PWQHWNVLEK TEEAEKTPVG S CFLAQPES GRRAEYSPCR GNTLSRIYVE NDFSWDKRYC EAGFSSVVTQ AGELVLGAPG GYYFLGLLAQ APVADIFSSY RP GILLWHV SSQSLSFDSS NPEYFDGYWG YSVAVGEFDG DLNTTEYVVG APTWSWTLGA VEILDSYYQR LHRLRGEQMA SYF GHSVAV TDVNGDGRHD LLVGAPLYME SRADRKLAEV GRVYLFLQPR GPHALGAPSL LLTGTQLYGR FGSAIAPLGD LDRD GYNDI AVAAPYGGPS GRGQVLVFLG QSEGLRSRPS QVLDSPFPTG SAFGFSLRGA VDIDDNGYPD LIVGAYGANQ VAVYR AQPV VKASVQLLVQ DSLNPAVKSC VLPQTKTPVS CFNIQMCVGA TGHNIPQKLS LNAELQLDRQ KPRQGRRVLL LGSQQA GTT LNLDLGGKHS PICHTTMAFL RDEADFRDKL SPIVLSLNVS LPPTEAGMAP AVVLHGDTHV QEQTRIVLDC GEDDVCV PQ LQLTASVTGS PLLVGADNVL ELQMDAANEG EGAYEAELAV HLPQGAHYMR ALSNVEGFER LICNQKKENE TRVVLCEL G NPMKKNAQIG IAMLVSVGNL EEAGESVSFQ LQIRSKNSQN PNSKIVLLDV PVRAEAQVEL RGNSFPASLV VAAEEGERE QNSLDSWGPK VEHTYELHNN GPGTVNGLHL SIHLPGQSQP SDLLYILDIQ PQGGLQCFPQ PPVNPLKVDW GLPIPSPSPI HPAHHKRDR RQIFLPEPEQ PSRLQDPVLV SCDSAPCTVV QCDLQEMARG QRAMVTVLAF LWLPSLYQRP LDQFVLQSHA W FNV |
-Macromolecule #2: Integrin beta-3
Macromolecule | Name: Integrin beta-3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 75.974828 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MRARPRPRPL WATVLALGAL AGVGVGGPNI CTTRGVSSCQ QCLAVSPMCA WCSDEALPLG SPRCDLKENL LKDNCAPESI EFPVSEARV LEDRPLSDKG SGDSSQVTQV SPQRIALRLR PDDSKNFSIQ VRQVEDYPVD IYYLMDLSYS MKDDLWSIQN L GTKLATQM ...String: MRARPRPRPL WATVLALGAL AGVGVGGPNI CTTRGVSSCQ QCLAVSPMCA WCSDEALPLG SPRCDLKENL LKDNCAPESI EFPVSEARV LEDRPLSDKG SGDSSQVTQV SPQRIALRLR PDDSKNFSIQ VRQVEDYPVD IYYLMDLSYS MKDDLWSIQN L GTKLATQM RKLTSNLRIG FGAFVDKPVS PYMYISPPEA LENPCYDMKT TCLPMFGYKH VLTLTDQVTR FNEEVKKQSV SR NRDAPEG GFDAIMQATV CDEKIGWRND ASHLLVFTTD AKTHIALDGR LAGIVQPNDG QCHVGSDNHY SASTTMDYPS LGL MTEKLS QKNINLIFAV TENVVNLYQN YSELIPGTTV GVLSMDSSNV LQLIVDAYGK IRSKVELEVR DLPEELSLSF NATC LNNEV IPGLKSCMGL KIGDTVSFSI EAKVRGCPQE KEKSFTIKPV GFKDSLIVQV TFDCDCACQA QAEPNSHRCN NGNGT FECG VCRCGPGWLG SQCECSEEDY RPSQQDECSP REGQPVCSQR GECLCGQCVC HSSDFGKITG KYCECDDFSC VRYKGE MCS GHGQCSCGDC LCDSDWTGYY CNCTTRTDTC MSSNGLLCSG RGKCECGSCV CIQPGSYGDT CEKCPTCPDA CTFKKEC VE CKKFDRGALH DENTCNRYCR DEIESVKELK DTGKDAVNCT YKNEDDCV |
-Macromolecule #3: Abciximab, heavy chain
Macromolecule | Name: Abciximab, heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 24.161119 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: EVQLQQSGTV LARPGASVKM SCEASGYTFT NYWMHWVKQR PGQGLEWIGA IYPGNSDTSY IQKFKGKAKL TAVTSTTSVY MELSSLTNE DSAVYYCTLY DGYYVFAYWG QGTLVTVSAA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW N SGALTSGV ...String: EVQLQQSGTV LARPGASVKM SCEASGYTFT NYWMHWVKQR PGQGLEWIGA IYPGNSDTSY IQKFKGKAKL TAVTSTTSVY MELSSLTNE DSAVYYCTLY DGYYVFAYWG QGTLVTVSAA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW N SGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTH |
-Macromolecule #4: Abciximab, light chain
Macromolecule | Name: Abciximab, light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 23.501986 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: EIVLTQSPVT LSVTPGDSVS LSCRASRDIS NNLHWFQQTS HESPRLLIKY ASQSMSGIPS RFSGSGSGTD FTLSINSVET EDFGMYFCQ QTNSWPYTFG GGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String: EIVLTQSPVT LSVTPGDSVS LSCRASRDIS NNLHWFQQTS HESPRLLIKY ASQSMSGIPS RFSGSGSGTD FTLSINSVET EDFGMYFCQ QTNSWPYTFG GGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC |
-Macromolecule #5: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 6 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Macromolecule #6: MAGNESIUM ION
Macromolecule | Name: MAGNESIUM ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: MG |
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Molecular weight | Theoretical: 24.305 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.1 mg/mL |
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Buffer | pH: 7.4 |
Vitrification | Cryogen name: NITROGEN |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1161396 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |