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- PDB-9dax: The structure of AlphaIIbbeta3 in apo state -

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Basic information

Entry
Database: PDB / ID: 9dax
TitleThe structure of AlphaIIbbeta3 in apo state
Components
  • Integrin alpha-IIb
  • Integrin beta-3
KeywordsBLOOD CLOTTING / alphaIIbbeta3 integrin / platelet aggregation / clot retraction
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 / maintenance of postsynaptic specialization structure / alphav-beta3 integrin-vitronectin complex / regulation of extracellular matrix organization ...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 / maintenance of postsynaptic specialization structure / alphav-beta3 integrin-vitronectin complex / regulation of extracellular matrix organization / positive regulation of glomerular mesangial cell proliferation / platelet alpha granule membrane / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / alphav-beta3 integrin-PKCalpha complex / fibrinogen binding / blood coagulation, fibrin clot formation / alphav-beta3 integrin-HMGB1 complex / vascular endothelial growth factor receptor 2 binding / negative regulation of lipid transport / positive regulation of vascular endothelial growth factor signaling pathway / regulation of release of sequestered calcium ion into cytosol / Elastic fibre formation / mesodermal cell differentiation / glycinergic synapse / cell-substrate junction assembly / alphav-beta3 integrin-IGF-1-IGF1R complex / platelet-derived growth factor receptor binding / positive regulation of bone resorption / filopodium membrane / extracellular matrix binding / negative regulation of low-density lipoprotein particle clearance / angiogenesis involved in wound healing / positive regulation of vascular endothelial growth factor receptor signaling pathway / regulation of bone resorption / apolipoprotein A-I-mediated signaling pathway / positive regulation of cell adhesion mediated by integrin / positive regulation of leukocyte migration / apoptotic cell clearance / wound healing, spreading of epidermal cells / positive regulation of fibroblast migration / integrin complex / heterotypic cell-cell adhesion / positive regulation of smooth muscle cell migration / smooth muscle cell migration / Molecules associated with elastic fibres / positive regulation of cell-matrix adhesion / negative chemotaxis / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / Syndecan interactions / cell adhesion mediated by integrin / cellular response to insulin-like growth factor stimulus / p130Cas linkage to MAPK signaling for integrins / positive regulation of osteoblast proliferation / regulation of postsynaptic neurotransmitter receptor internalization / protein disulfide isomerase activity / microvillus membrane / cell-substrate adhesion / platelet-derived growth factor receptor signaling pathway / PECAM1 interactions / GRB2:SOS provides linkage to MAPK signaling for Integrins / TGF-beta receptor signaling activates SMADs / lamellipodium membrane / negative regulation of macrophage derived foam cell differentiation / fibronectin binding / negative regulation of lipid storage / ECM proteoglycans / Integrin cell surface interactions / positive regulation of T cell migration / negative regulation of endothelial cell apoptotic process / coreceptor activity / cell adhesion molecule binding / cellular response to platelet-derived growth factor stimulus / positive regulation of endothelial cell proliferation / Integrin signaling / positive regulation of smooth muscle cell proliferation / positive regulation of substrate adhesion-dependent cell spreading / embryo implantation / positive regulation of endothelial cell migration / substrate adhesion-dependent cell spreading / protein kinase C binding / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / cell-matrix adhesion / response to activity / Signal transduction by L1 / integrin-mediated signaling pathway / regulation of actin cytoskeleton organization / wound healing / cellular response to mechanical stimulus / Signaling by high-kinase activity BRAF mutants / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / MAP2K and MAPK activation / cell-cell adhesion / platelet activation / platelet aggregation / VEGFA-VEGFR2 Pathway / ruffle membrane / integrin binding / cellular response to xenobiotic stimulus / positive regulation of fibroblast proliferation
Similarity search - Function
Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / Integrin beta tail domain / Integrin beta subunit, cytoplasmic domain / Integrin beta cytoplasmic domain / Integrin_b_cyt / : / Integrin alpha Ig-like domain 3 / Integrin EGF domain / Integrin beta subunit, tail ...Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / Integrin beta tail domain / Integrin beta subunit, cytoplasmic domain / Integrin beta cytoplasmic domain / Integrin_b_cyt / : / Integrin alpha Ig-like domain 3 / Integrin EGF domain / Integrin beta subunit, tail / Integrin beta tail domain superfamily / Integrin_B_tail / EGF-like domain, extracellular / EGF-like domain / Integrin alpha cytoplasmic region / Integrins beta chain EGF (I-EGF) domain profile. / Integrin beta subunit, VWA domain / Integrin beta subunit / Integrin beta N-terminal / Integrin beta chain VWA domain / Integrin plexin domain / Integrins beta chain EGF (I-EGF) domain signature. / Integrin beta subunits (N-terminal portion of extracellular region) / Integrin alpha-2 / Integrin alpha Ig-like domain 1 / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / Integrins alpha chain signature. / Integrin alpha chain / Integrin alpha beta-propellor / : / Integrin alpha Ig-like domain 2 / FG-GAP repeat profile. / Integrin alpha (beta-propellor repeats). / FG-GAP repeat / FG-GAP repeat / Integrin alpha, N-terminal / Integrin domain superfamily / PSI domain / domain found in Plexins, Semaphorins and Integrins / von Willebrand factor A-like domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2.
Similarity search - Domain/homology
Integrin beta-3 / Integrin alpha-IIb
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsWalz, T. / Coller, B.S. / Wang, J.L. / Buitrago, L. / Wang, L. / Li, J.H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)5R01HL019278-48 United States
CitationJournal: Blood Adv / Year: 2025
Title: An αIIbβ3 ligand-mimetic murine monoclonal antibody that produces platelet activation by engaging the FcγIIa receptor.
Authors: Jialing Wang / Lorena Buitrago / Lu Wang / Jihong Li / Thomas Walz / Barry S Coller /
Abstract: To produce a murine monoclonal antibody (mAb) that binds to glycoprotein IIb/IIIa (αIIbβ3) and inhibits clot retraction (CR), we immunized mice with human platelets and tested hybridoma ...To produce a murine monoclonal antibody (mAb) that binds to glycoprotein IIb/IIIa (αIIbβ3) and inhibits clot retraction (CR), we immunized mice with human platelets and tested hybridoma supernatants for their ability to bind to αIIbβ3 and inhibit CR. The immunoglobulin G1 (IgG1) mAb R6H8 completely inhibited CR at 20 μg/mL. Paradoxically, at 5 μg/mL, R6H8 initiated platelet aggregation and induced P-selectin expression, fibrinogen binding, and PAC-1 binding. At 20 μg/mL, however, R6H8 completely inhibited aggregation induced by thrombin PAR-1 receptor activating peptide SFLLRN (T6; 25 μg/mL) and T6-induced fibrinogen and PAC-1 binding to platelets. Platelet aggregation induced by R6H8 was inhibited by mAb IV.3, which blocks the FcγIIa receptor (FcγRIIa), and the Fab fragment of R6H8 did not induce platelet aggregation, suggesting that R6H8 binds to both αIIbβ3 and FcγRIIa. Cryogenic electron microscopy analysis of the R6H8 Fab-αIIbβ3 complex revealed that R6H8 (1) binds to the αIIbβ3 RGD binding pocket via an Arg-Tyr-Asp (RYD) sequence in its heavy chain complementarity-determining region 3; (2) interacts with β3 Asp126, producing a reorientation of Asp126 and loss of the adjacent to metal ion-dependent adhesion site Ca2+; and (3) initiates swing-out of the β3 hybrid domain. We conclude that R6H8 is an αIIbβ3 ligand-mimetic mAb that activates platelets via FcγRIIa at low concentrations and potently inhibits platelet aggregation and CR at high concentrations. R6H8 simulates the actions of a number of pathological antibodies, including platelet-activating antibodies developed after therapy with αIIbβ3 inhibitors and platelet-activating antibodies in heparin-induced thrombocytopenia and vaccine-induced immune thrombotic thrombocytopenia. As such, it may be a valuable reagent for better understanding these disorders and identifying potential therapies.
History
DepositionAug 22, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 9, 2025Provider: repository / Type: Initial release
Revision 1.0Apr 9, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 9, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.1May 14, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
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Revision 1.2Jul 23, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Integrin alpha-IIb
B: Integrin beta-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)194,8509
Polymers194,5852
Non-polymers2657
Water1086
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Integrin alpha-IIb / GPalpha IIb / GPIIb / Platelet membrane glycoprotein IIb


Mass: 110106.391 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P08514
#2: Protein Integrin beta-3 / Platelet membrane glycoprotein IIIa / GPIIIa


Mass: 84478.500 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P05106
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: AlphaIIbbeta3 integrin in apo state / Type: COMPLEX / Details: AlphaIIbbeta3 is platelet-derived / Entity ID: #1-#2 / Source: NATURAL
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.2 MDaYES
210.113 MDaNO
310.087 MDaYES
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 0.012 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 54 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 146339 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0096526
ELECTRON MICROSCOPYf_angle_d1.0348867
ELECTRON MICROSCOPYf_dihedral_angle_d4.754902
ELECTRON MICROSCOPYf_chiral_restr0.045970
ELECTRON MICROSCOPYf_plane_restr0.0071167

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