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- PDB-6avq: The Therapeutic Antibody LM609 Selectively Inhibits Ligand Bindin... -
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Basic information
Entry | Database: PDB / ID: 6avq | |||||||||
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Title | The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance | |||||||||
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![]() | SIGNALING PROTEIN / alpha-V beta-3 integrin / LM609 / vitaxin / abegrin | |||||||||
Function / homology | ![]() 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 / 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 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 / 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 / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / positive regulation of cell adhesion / ECM proteoglycans / voltage-gated calcium channel activity / positive regulation of bone resorption / 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 / 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 / substrate adhesion-dependent cell spreading Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / negative staining / Resolution: 35 Å | |||||||||
![]() | Borst, A.J. / James, Z.N. / Zagotta, W.N. / Ginsberg, M. / Rey, F.A. / DiMaio, F. / Backovic, M. / Veesler, D. | |||||||||
Funding support | ![]()
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![]() | ![]() 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: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 308.5 KB | Display | ![]() |
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PDB format | ![]() | 210.6 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 7011MC ![]() 7012C ![]() 7013C ![]() 5opyC ![]() 6avrC ![]() 6avuC C: citing same article ( M: map data used to model this data |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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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.) ![]() ![]() ![]() |
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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.) ![]() ![]() ![]() |
#3: Antibody | Mass: 27223.100 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
#4: Antibody | Mass: 23628.977 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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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: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
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 |
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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) |
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Processing
EM software |
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CTF correction | Type: NONE | |||||||||
Symmetry | Point symmetry: C1 (asymmetric) | |||||||||
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 |