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- EMDB-40989: Cryo-EM Structures of Full-length Integrin alphaIIbbeta3 in Nativ... -

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Entry
Database: EMDB / ID: EMD-40989
TitleCryo-EM Structures of Full-length Integrin alphaIIbbeta3 in Native Lipids
Map data
Sample
  • Complex: full length integrin alphaIIbbeta3
    • Protein or peptide: Integrin alpha-IIb
    • Protein or peptide: Integrin beta-3Integrin beta 3
  • Ligand: CALCIUM IONCalcium
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: MAGNESIUM ION
  • Ligand: water
Keywordscomplex / 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
Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / Integrin beta subunit, cytoplasmic domain / Integrin beta cytoplasmic domain / Integrin_b_cyt / : / Integrin alpha Ig-like domain 3 / Integrin beta tail domain / Integrin beta subunit, tail / Integrin beta tail domain superfamily ...Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / Integrin beta subunit, cytoplasmic domain / Integrin beta cytoplasmic domain / Integrin_b_cyt / : / Integrin alpha Ig-like domain 3 / Integrin beta tail domain / Integrin beta subunit, tail / Integrin beta tail domain superfamily / Integrin_B_tail / Integrin beta subunit, VWA domain / Integrin beta subunit / Integrin beta N-terminal / Integrin beta chain VWA domain / Integrin plexin domain / Integrins beta chain cysteine-rich domain signature. / Integrin beta subunits (N-terminal portion of extracellular region) / Integrin alpha cytoplasmic region / EGF-like domain, extracellular / EGF-like domain / Integrin alpha-2 / Integrin alpha Ig-like domain 1 / : / Integrin alpha Ig-like domain 2 / Integrin alpha chain / Integrin alpha beta-propellor / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / Integrins alpha chain signature. / FG-GAP repeat profile. / Integrin alpha (beta-propellor repeats). / FG-GAP repeat / FG-GAP repeat / Integrin domain superfamily / Integrin alpha, N-terminal / PSI domain / domain found in Plexins, Semaphorins and Integrins / von Willebrand factor A-like domain superfamily / EGF-like domain signature 2. / EGF-like domain signature 1.
Similarity search - Domain/homology
Integrin beta-3 / Integrin alpha-IIb
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsAdair B / Xiong JP / Yeager M / Arnaout MA
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL141366 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK088327 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM084545 United States
CitationJournal: 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
DepositionJun 6, 2023-
Header (metadata) releaseJul 26, 2023-
Map releaseJul 26, 2023-
UpdateMay 1, 2024-
Current statusMay 1, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40989.png

Downloads & links

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Map

FileDownload / File: emd_40989.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.26146162 - 0.9485184
Average (Standard dev.)0.000078566605 (±0.015484845)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 324.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40989_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40989_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : full length integrin alphaIIbbeta3

EntireName: full length integrin alphaIIbbeta3
Components
  • Complex: full length integrin alphaIIbbeta3
    • Protein or peptide: Integrin alpha-IIb
    • Protein or peptide: Integrin beta-3Integrin beta 3
  • Ligand: CALCIUM IONCalcium
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: MAGNESIUM ION
  • Ligand: water

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Supramolecule #1: full length integrin alphaIIbbeta3

SupramoleculeName: full length integrin alphaIIbbeta3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Integrin alpha-IIb

MacromoleculeName: Integrin alpha-IIb / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 110.106391 KDa
SequenceString: 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

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Macromolecule #2: Integrin beta-3

MacromoleculeName: Integrin beta-3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.4785 KDa
SequenceString: 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

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Macromolecule #7: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 7 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #9: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 9 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #10: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 10 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #11: water

MacromoleculeName: water / type: ligand / ID: 11 / Number of copies: 6 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 7.4 / Details: TBS/1mM CaCl2
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 0.27 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 81000
Specialist opticsEnergy filter - Name: GIF Quantum ER / Energy filter - Slit width: 10 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 11947 / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4477836
Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.2.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.2.1) / Number images used: 117126
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

3fcs

source_name: PDB, initial_model_type: experimental model

2k9j

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8t2v:
Cryo-EM Structures of Full-length Integrin alphaIIbbeta3 in Native Lipids

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