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- PDB-6avr: Human alpha-V beta-3 Integrin (intermediate conformation) in comp... -

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Basic information

Entry
Database: PDB / ID: 6avr
TitleHuman alpha-V beta-3 Integrin (intermediate conformation) in complex with the therapeutic antibody LM609
Components
  • Fab LM609 heavy chain
  • Fab LM609 light chain
  • Integrin alpha-VIntegrin alpha V
  • Integrin beta-3Integrin beta 3
KeywordsSIGNALING PROTEIN / alpha-V beta-3 integrin / LM609 / vitaxin / abegrin
Function / homology
Function and homology information


entry of symbiont into host cell by promotion of host phagocytosis / integrin alphav-beta5 complex / transforming growth factor-beta secretion / integrin alphav-beta8 complex / integrin alphav-beta6 complex / opsonin binding / negative regulation of entry of bacterium into host cell / regulation of transforming growth factor beta activation / extracellular matrix protein binding / tube development ...entry of symbiont into host cell by promotion of host phagocytosis / integrin alphav-beta5 complex / transforming growth factor-beta secretion / integrin alphav-beta8 complex / integrin alphav-beta6 complex / opsonin binding / negative regulation of entry of bacterium into host cell / regulation of transforming growth factor beta activation / extracellular matrix protein binding / tube development / regulation of serotonin uptake / alphav-beta3 integrin-vitronectin complex / platelet alpha granule membrane / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / negative regulation of low-density lipoprotein particle receptor biosynthetic process / alphav-beta3 integrin-PKCalpha complex / vascular endothelial growth factor receptor 2 binding / alphav-beta3 integrin-HMGB1 complex / negative regulation of lipid transport / transforming growth factor beta binding / regulation of postsynaptic neurotransmitter receptor internalization / apolipoprotein A-I-mediated signaling pathway / alphav-beta3 integrin-IGF-1-IGF1R complex / regulation of bone resorption / platelet-derived growth factor receptor binding / mesodermal cell differentiation / regulation of phagocytosis / negative regulation of lipid storage / extracellular matrix binding / angiogenesis involved in wound healing / filopodium membrane / protein disulfide isomerase activity / heterotypic cell-cell adhesion / microvillus membrane / positive regulation of vascular endothelial growth factor receptor signaling pathway / endodermal cell differentiation / apoptotic cell clearance / integrin complex / cell adhesion mediated by integrin / negative chemotaxis / smooth muscle cell migration / cell-substrate adhesion / positive regulation of osteoblast proliferation / voltage-gated calcium channel activity / coreceptor activity / negative regulation of macrophage derived foam cell differentiation / positive regulation of cell adhesion / lamellipodium membrane / fibronectin binding / specific granule membrane / phagocytic vesicle / substrate adhesion-dependent cell spreading / vasculogenesis / calcium ion transmembrane transport / positive regulation of endothelial cell migration / ERK1 and ERK2 cascade / cell-matrix adhesion / cell adhesion molecule binding / positive regulation of endothelial cell proliferation / protein kinase C binding / activation of protein kinase activity / extrinsic apoptotic signaling pathway in absence of ligand / platelet aggregation / regulation of protein localization / negative regulation of extrinsic apoptotic signaling pathway / ruffle membrane / integrin-mediated signaling pathway / antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent / virus receptor activity / melanosome / cell migration / vascular endothelial growth factor receptor signaling pathway / postsynaptic membrane / positive regulation of cytosolic calcium ion concentration / cell-cell junction / platelet degranulation / integrin binding / platelet activation / positive regulation of peptidyl-tyrosine phosphorylation / wound healing / extracellular matrix organization / leukocyte migration / angiogenesis / viral entry into host cell / receptor complex / protease binding / blood coagulation / external side of plasma membrane / cell adhesion / positive regulation of cell migration / positive regulation of protein phosphorylation / synapse / glutamatergic synapse / focal adhesion / neutrophil degranulation / positive regulation of cell population proliferation / integral component of plasma membrane / cell surface / enzyme binding
Integrin beta epidermal growth factor like domain 1 / Integrin alpha, N-terminal / Integrin alpha chain / Integrin beta subunit, VWA domain / Integrin beta subunit, tail / FG-GAP repeat / Integrin alpha beta-propellor / Integrin alpha-2 / Integrin beta subunit, cytoplasmic domain / Integrin beta subunit ...Integrin beta epidermal growth factor like domain 1 / Integrin alpha, N-terminal / Integrin alpha chain / Integrin beta subunit, VWA domain / Integrin beta subunit, tail / FG-GAP repeat / Integrin alpha beta-propellor / Integrin alpha-2 / Integrin beta subunit, cytoplasmic domain / Integrin beta subunit / PSI domain / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / Integrin beta-3 subunit / EGF-like domain, extracellular / Integrin domain superfamily / Integrin beta chain VWA domain / Integrin beta N-terminal / EGF-like domain / Integrin beta tail domain / Integrin plexin domain / Integrin alpha / Integrin beta, epidermal growth factor-like domain 1 / von Willebrand factor A-like domain superfamily / FG-GAP repeat / Integrin beta tail domain superfamily
Integrin beta-3 / Integrin alpha-V
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / negative staining / Resolution: 35 Å
AuthorsBorst, A.J. / James, Z.N. / Zagotta, W.N. / Ginsberg, M. / Rey, F.A. / DiMaio, F. / Backovic, M. / Veesler, D.
CitationJournal: 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.
Validation Report
SummaryFull reportAbout validation report
History
DepositionSep 4, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 1, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jul 18, 2018Group: Data collection / Category: em_software / Item: _em_software.name

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Structure visualization

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Assembly

Deposited unit
A: Integrin alpha-V
B: Integrin beta-3
H: Fab LM609 heavy chain
L: Fab LM609 light chain


Theoretical massNumber of molelcules
Total (without water)233,2694
Polymers233,2694
Non-polymers00
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Integrin alpha-V / Integrin alpha V / Vitronectin receptor / Vitronectin receptor subunit alpha


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
#2: Protein Integrin beta-3 / Integrin beta 3 / Platelet membrane glycoprotein IIIa / GPIIIa


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 Fab LM609 heavy chain


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 Fab LM609 light chain


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)

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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: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
Type: COMPLEX / Entity ID: 1, 2, 3, 4 / Source: RECOMBINANT
Molecular weightValue: 0.23 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Drosophila melanogaster (fruit fly)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: NO
EM stainingType: NEGATIVE / Material: Uranyl formate
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat 2/0.5

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Electron microscopy imaging

MicroscopyModel: FEI TECNAI 12
Electron gunElectron source: LAB6 / Accelerating voltage: 120 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN ULTRASCAN 4000 (4k x 4k)

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Processing

EM software
IDNameCategory
7UCSF Chimeramodel fitting
13Rosettamodel refinement
CTF correctionType: NONE
3D reconstructionResolution: 35 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 650 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL

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