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Yorodumi- EMDB-40988: Cryo-EM Structures of Full-length Integrin alphaIIbbeta3 in Nativ... -
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-Basic information
Entry | Database: EMDB / ID: EMD-40988 | ||||||||||||
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Title | Cryo-EM Structures of Full-length Integrin alphaIIbbeta3 in Native Lipids complexed with Eptifibatide | ||||||||||||
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Sample |
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Keywords | complex / open headpiece / CELL ADHESION | ||||||||||||
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 / regulation of postsynaptic neurotransmitter receptor diffusion trapping / alphav-beta3 integrin-vitronectin complex / maintenance of postsynaptic specialization structure / 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 / regulation of postsynaptic neurotransmitter receptor diffusion trapping / alphav-beta3 integrin-vitronectin complex / maintenance of postsynaptic specialization structure / 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 / glycinergic synapse / alphav-beta3 integrin-HMGB1 complex / vascular endothelial growth factor receptor 2 binding / blood coagulation, fibrin clot formation / negative regulation of lipid transport / negative regulation of low-density lipoprotein receptor activity / Elastic fibre formation / regulation of release of sequestered calcium ion into cytosol / cell-substrate junction assembly / mesodermal cell differentiation / angiogenesis involved in wound healing / alphav-beta3 integrin-IGF-1-IGF1R complex / platelet-derived growth factor receptor binding / filopodium membrane / extracellular matrix binding / positive regulation of fibroblast migration / positive regulation of vascular endothelial growth factor receptor signaling pathway / regulation of postsynaptic neurotransmitter receptor internalization / apolipoprotein A-I-mediated signaling pathway / regulation of bone resorption / wound healing, spreading of epidermal cells / apoptotic cell clearance / heterotypic cell-cell adhesion / positive regulation of cell adhesion mediated by integrin / integrin complex / Molecules associated with elastic fibres / cellular response to insulin-like growth factor stimulus / positive regulation of leukocyte migration / cell adhesion mediated by integrin / positive regulation of cell-matrix adhesion / smooth muscle cell migration / microvillus membrane / Syndecan interactions / negative chemotaxis / p130Cas linkage to MAPK signaling for integrins / cellular response to platelet-derived growth factor stimulus / cell-substrate adhesion / protein disulfide isomerase activity / positive regulation of smooth muscle cell migration / activation of protein kinase activity / positive regulation of osteoblast proliferation / TGF-beta receptor signaling activates SMADs / PECAM1 interactions / lamellipodium membrane / GRB2:SOS provides linkage to MAPK signaling for Integrins / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / platelet-derived growth factor receptor signaling pathway / fibronectin binding / ECM proteoglycans / positive regulation of bone resorption / positive regulation of T cell migration / Integrin cell surface interactions / coreceptor activity / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / embryo implantation / positive regulation of endothelial cell proliferation / cell adhesion molecule binding / Integrin signaling / substrate adhesion-dependent cell spreading / cell-matrix adhesion / positive regulation of endothelial cell migration / protein kinase C binding / response to activity / Signal transduction by L1 / integrin-mediated signaling pathway / regulation of actin cytoskeleton organization / positive regulation of smooth muscle cell proliferation / Signaling by high-kinase activity BRAF mutants / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / MAP2K and MAPK activation / wound healing / cell-cell adhesion / platelet aggregation / platelet activation / ruffle membrane / VEGFA-VEGFR2 Pathway / 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 / regulation of protein localization Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) / human (human) / synthetic construct (others) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.1 Å | ||||||||||||
Authors | Adair B / Xiong JP / Yeager M / Arnaout MA | ||||||||||||
Funding support | United States, 3 items
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Citation | Journal: Nat Commun / Year: 2023 Title: Cryo-EM structures of full-length integrin αIIbβ3 in native lipids. Authors: Brian D Adair / Jian-Ping Xiong / Mark Yeager / M Amin Arnaout / Abstract: Platelet integrin αIIbβ3 is maintained in a bent inactive state (low affinity to physiologic ligand), but can rapidly switch to a ligand-competent (high-affinity) state in response to intracellular ...Platelet integrin αIIbβ3 is maintained in a bent inactive state (low affinity to physiologic ligand), but can rapidly switch to a ligand-competent (high-affinity) state in response to intracellular signals ("inside-out" activation). Once bound, ligands drive proadhesive "outside-in" signaling. Anti-αIIbβ3 drugs like eptifibatide can engage the inactive integrin directly, inhibiting thrombosis but inadvertently impairing αIIbβ3 hemostatic functions. Bidirectional αIIbβ3 signaling is mediated by reorganization of the associated αIIb and β3 transmembrane α-helices, but the underlying changes remain poorly defined absent the structure of the full-length receptor. We now report the cryo-EM structures of full-length αIIbβ3 in its apo and eptifibatide-bound states in native cell-membrane nanoparticles at near-atomic resolution. The apo form adopts the bent inactive state but with separated transmembrane α-helices, and a fully accessible ligand-binding site that challenges the model that this site is occluded by the plasma membrane. Bound eptifibatide triggers dramatic conformational changes that may account for impaired hemostasis. These results advance our understanding of integrin structure and function and may guide development of safer inhibitors. | ||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_40988.map.gz | 32.2 MB | EMDB map data format | |
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Header (meta data) | emd-40988-v30.xml emd-40988.xml | 20.7 KB 20.7 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_40988_fsc.xml | 8.4 KB | Display | FSC data file |
Images | emd_40988.png | 66.4 KB | ||
Others | emd_40988_half_map_1.map.gz emd_40988_half_map_2.map.gz | 59.3 MB 59.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-40988 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-40988 | HTTPS FTP |
-Related structure data
Related structure data | 8t2uMC 8t2vC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_40988.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.08 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_40988_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_40988_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : complex of integrin alphaIIbbeta3 with eptifibatide
Entire | Name: complex of integrin alphaIIbbeta3 with eptifibatide |
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Components |
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-Supramolecule #1: complex of integrin alphaIIbbeta3 with eptifibatide
Supramolecule | Name: complex of integrin alphaIIbbeta3 with eptifibatide / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | 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: human (human) |
Molecular weight | Theoretical: 110.106391 KDa |
Sequence | String: LNLDPVQLTF YAGPNGSQFG FSLDFHKDSH GRVAIVVGAP RTLGPSQEET GGVFLCPWRA EGGQCPSLLF DLRDETRNVG SQTLQTFKA RQGLGASVVS WSDVIVACAP WQHWNVLEKT EEAEKTPVGS CFLAQPESGR RAEYSPCRGN TLSRIYVEND F SWDKRYCE ...String: LNLDPVQLTF YAGPNGSQFG FSLDFHKDSH GRVAIVVGAP RTLGPSQEET GGVFLCPWRA EGGQCPSLLF DLRDETRNVG SQTLQTFKA RQGLGASVVS WSDVIVACAP WQHWNVLEKT EEAEKTPVGS CFLAQPESGR RAEYSPCRGN TLSRIYVEND F SWDKRYCE AGFSSVVTQA GELVLGAPGG YYFLGLLAQA PVADIFSSYR PGILLWHVSS QSLSFDSSNP EYFDGYWGYS VA VGEFDGD LNTTEYVVGA PTWSWTLGAV EILDSYYQRL HRLRGEQMAS YFGHSVAVTD VNGDGRHDLL VGAPLYMESR ADR KLAEVG RVYLFLQPRG PHALGAPSLL LTGTQLYGRF GSAIAPLGDL DRDGYNDIAV AAPYGGPSGR GQVLVFLGQS EGLR SRPSQ VLDSPFPTGS AFGFSLRGAV DIDDNGYPDL IVGAYGANQV AVYRAQPVVK ASVQLLVQDS LNPAVKSCVL PQTKT PVSC FNIQMCVGAT GHNIPQKLSL NAELQLDRQK PRQGRRVLLL GSQQAGTTLN LDLGGKHSPI CHTTMAFLRD EADFRD KLS PIVLSLNVSL PPTEAGMAPA VVLHGDTHVQ EQTRIVLDCG EDDVCVPQLQ LTASVTGSPL LVGADNVLEL QMDAANE GE GAYEAELAVH LPQGAHYMRA LSNVEGFERL ICNQKKENET RVVLCELGNP MKKNAQIGIA MLVSVGNLEE AGESVSFQ L QIRSKNSQNP NSKIVLLDVP VRAEAQVELR GNSFPASLVV AAEEGEREQN SLDSWGPKVE HTYELHNNGP GTVNGLHLS IHLPGQSQPS DLLYILDIQP QGGLQCFPQP PVNPLKVDWG LPIPSPSPIH PAHHKRDRRQ IFLPEPEQPS RLQDPVLVSC DSAPCTVVQ CDLQEMARGQ RAMVTVLAFL WLPSLYQRPL DQFVLQSHAW FNVSSLPYAV PPLSLPRGEA QVWTQLLRAL E ERAIPIWW VLVGVLGGLL LLTILVLAMW KVGFFKRNRP PLEEDDEEGE UniProtKB: Integrin alpha-IIb |
-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: human (human) |
Molecular weight | Theoretical: 84.4785 KDa |
Sequence | String: GPNICTTRGV SSCQQCLAVS PMCAWCSDEA LPLGSPRCDL KENLLKDNCA PESIEFPVSE ARVLEDRPLS DKGSGDSSQV TQVSPQRIA LRLRPDDSKN FSIQVRQVED YPVDIYYLMD LSYSMKDDLW SIQNLGTKLA TQMRKLTSNL RIGFGAFVDK P VSPYMYIS ...String: GPNICTTRGV SSCQQCLAVS PMCAWCSDEA LPLGSPRCDL KENLLKDNCA PESIEFPVSE ARVLEDRPLS DKGSGDSSQV TQVSPQRIA LRLRPDDSKN FSIQVRQVED YPVDIYYLMD LSYSMKDDLW SIQNLGTKLA TQMRKLTSNL RIGFGAFVDK P VSPYMYIS PPEALENPCY DMKTTCLPMF GYKHVLTLTD QVTRFNEEVK KQSVSRNRDA PEGGFDAIMQ ATVCDEKIGW RN DASHLLV FTTDAKTHIA LDGRLAGIVQ PNDGQCHVGS DNHYSASTTM DYPSLGLMTE KLSQKNINLI FAVTENVVNL YQN YSELIP GTTVGVLSMD SSNVLQLIVD AYGKIRSKVE LEVRDLPEEL SLSFNATCLN NEVIPGLKSC MGLKIGDTVS FSIE AKVRG CPQEKEKSFT IKPVGFKDSL IVQVTFDCDC ACQAQAEPNS HRCNNGNGTF ECGVCRCGPG WLGSQCECSE EDYRP SQQD ECSPREGQPV CSQRGECLCG QCVCHSSDFG KITGKYCECD DFSCVRYKGE MCSGHGQCSC GDCLCDSDWT GYYCNC TTR TDTCMSSNGL LCSGRGKCEC GSCVCIQPGS YGDTCEKCPT CPDACTFKKE CVECKKFDRG ALHDENTCNR YCRDEIE SV KELKDTGKDA VNCTYKNEDD CVVRFQYYED SSGKSILYVV EEPECPKGPD ILVVLLSVMG AILLIGLAAL LIWKLLIT I HDRKEFAKFE EERARAKWDT ANNPLYKEAT STFTNITYRG T UniProtKB: Integrin beta-3 |
-Macromolecule #3: Eptifibatide
Macromolecule | Name: Eptifibatide / 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: 832.972 Da |
Sequence | String: (MPT)(HRG)GDWPC(NH2) |
-Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 2 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #8: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 8 / Number of copies: 6 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Macromolecule #9: MAGNESIUM ION
Macromolecule | Name: MAGNESIUM ION / type: ligand / ID: 9 / Number of copies: 1 / Formula: MG |
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Molecular weight | Theoretical: 24.305 Da |
-Macromolecule #10: water
Macromolecule | Name: water / type: ligand / ID: 10 / Number of copies: 2 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | cell |
-Sample preparation
Buffer | pH: 7.4 / Details: TBS/1mM CaCl2 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 0.27 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 81000 |
Specialist optics | Energy filter - Name: GIF Quantum ER / Energy filter - Slit width: 10 eV |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 9805 / Average electron dose: 50.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |