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Yorodumi- PDB-6avu: Human alpha-V beta-3 Integrin (open conformation) in complex with... -
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-Basic information
Entry | Database: PDB / ID: 6avu | ||||||
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Title | Human alpha-V beta-3 Integrin (open conformation) in complex with the therapeutic antibody LM609 | ||||||
Components |
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Keywords | SIGNALING PROTEIN / alpha-V beta-3 integrin / LM609 / vitaxin / abegrin | ||||||
Function / homology | Function and homology information integrin alphav-beta6 complex / integrin alphav-beta8 complex / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / opsonin binding / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) / extracellular matrix protein binding / tube development ...integrin alphav-beta6 complex / integrin alphav-beta8 complex / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / opsonin binding / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) / extracellular matrix protein binding / 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 / Laminin interactions / 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 / entry into host cell by a symbiont-containing vacuole / 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 / regulation of phagocytosis / 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 / transforming growth factor beta binding / platelet-derived growth factor receptor binding / filopodium membrane / extracellular matrix binding / positive regulation of small GTPase mediated signal transduction / 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 / negative regulation of macrophage derived foam cell differentiation / positive regulation of cell adhesion mediated by integrin / wound healing, spreading of epidermal cells / heterotypic cell-cell adhesion / negative regulation of lipid storage / integrin complex / Molecules associated with elastic fibres / positive regulation of intracellular signal transduction / 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 / positive regulation of bone resorption / 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 / endodermal cell differentiation / 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 / positive regulation of cell adhesion / ECM proteoglycans / voltage-gated calcium channel activity / positive regulation of T cell migration / vasculogenesis / Integrin cell surface interactions / coreceptor activity / negative regulation of endothelial cell apoptotic process / specific granule membrane / positive regulation of substrate adhesion-dependent cell spreading / extrinsic apoptotic signaling pathway in absence of ligand / Signal transduction by L1 / phagocytic vesicle / cell adhesion molecule binding / positive regulation of endothelial cell proliferation / ERK1 and ERK2 cascade / embryo implantation / positive regulation of endothelial cell migration / Integrin signaling Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / negative staining / Resolution: 35 Å | ||||||
Authors | Borst, A.J. / James, Z.N. / Zagotta, W.N. / Ginsberg, M. / Rey, F.A. / DiMaio, F. / Backovic, M. / Veesler, D. | ||||||
Citation | Journal: Structure / Year: 2017 Title: The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αβ Integrin via Steric Hindrance. Authors: Andrew J Borst / Zachary M James / William N Zagotta / Mark Ginsberg / Felix A Rey / Frank DiMaio / Marija Backovic / David Veesler / Abstract: The LM609 antibody specifically recognizes αβ integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II ...The LM609 antibody specifically recognizes αβ integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for αβ-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of αβ integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for αβ. Using single-particle electron microscopy, we show that LM609 binds at the interface between the β-propeller domain of the α chain and the βI domain of the β chain, near the RGD-binding site, of all observed integrin conformational states. Integrating these data with fluorescence size-exclusion chromatography, we demonstrate that LM609 sterically hinders access of large ligands to the RGD-binding pocket, without obstructing it. This work provides a structural framework to expedite future efforts utilizing LM609 as a diagnostic or therapeutic tool. | ||||||
History |
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-Structure visualization
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
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PDBx/mmCIF format | 6avu.cif.gz | 280.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6avu.ent.gz | 189.6 KB | Display | PDB format |
PDBx/mmJSON format | 6avu.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6avu_validation.pdf.gz | 655.1 KB | Display | wwPDB validaton report |
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Full document | 6avu_full_validation.pdf.gz | 656.6 KB | Display | |
Data in XML | 6avu_validation.xml.gz | 39.5 KB | Display | |
Data in CIF | 6avu_validation.cif.gz | 66.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/av/6avu ftp://data.pdbj.org/pub/pdb/validation_reports/av/6avu | HTTPS FTP |
-Related structure data
Related structure data | 7013MC 7011C 7012C 5opyC 6avqC 6avrC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 105894.188 Da / Num. of mol.: 1 / Fragment: UNP residues 31-987 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ITGAV, MSK8, VNRA, VTNR / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: P06756 |
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#2: Protein | Mass: 76523.125 Da / Num. of mol.: 1 / Fragment: UNP residues 27-718 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ITGB3, GP3A / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: P05106 |
#3: Antibody | Mass: 27223.100 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Drosophila melanogaster (fruit fly) |
#4: Antibody | Mass: 23628.977 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Drosophila melanogaster (fruit fly) |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609 Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Value: 0.23 MDa / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Drosophila melanogaster (fruit fly) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: NO |
EM staining | Type: NEGATIVE / Material: Uranyl formate |
Specimen support | Grid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat 2/0.5 |
-Electron microscopy imaging
Microscopy | Model: FEI TECNAI 12 |
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Electron gun | Electron source: LAB6 / Accelerating voltage: 120 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 30 e/Å2 / Film or detector model: GATAN ULTRASCAN 4000 (4k x 4k) |
-Processing
EM software |
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CTF correction | Type: NONE | |||||||||
3D reconstruction | Resolution: 35 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 650 / Symmetry type: POINT | |||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL |