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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-V
  • Integrin beta-3
KeywordsSIGNALING PROTEIN / alpha-V beta-3 integrin / LM609 / vitaxin / abegrin
Function / homology
Function and homology information


integrin alphav-beta8 complex / integrin alphav-beta6 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-beta8 complex / integrin alphav-beta6 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 / maintenance of postsynaptic specialization structure / alphav-beta3 integrin-vitronectin complex / regulation of extracellular matrix organization / positive regulation of glomerular mesangial cell proliferation / Laminin interactions / platelet alpha granule membrane / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / entry into host cell by a symbiont-containing vacuole / 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 / regulation of phagocytosis / 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 / positive regulation of bone resorption / platelet-derived growth factor receptor binding / transforming growth factor beta binding / positive regulation of small GTPase mediated signal transduction / 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 / apolipoprotein A-I-mediated signaling pathway / positive regulation of cell adhesion mediated by integrin / regulation of bone resorption / apoptotic cell clearance / wound healing, spreading of epidermal cells / positive regulation of fibroblast migration / integrin complex / positive regulation of smooth muscle cell migration / heterotypic cell-cell adhesion / smooth muscle cell migration / Molecules associated with elastic fibres / negative chemotaxis / positive regulation of cell-matrix adhesion / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / cell adhesion mediated by integrin / Syndecan interactions / positive regulation of osteoblast proliferation / p130Cas linkage to MAPK signaling for integrins / cellular response to insulin-like growth factor stimulus / regulation of postsynaptic neurotransmitter receptor internalization / protein disulfide isomerase activity / microvillus membrane / cell-substrate adhesion / platelet-derived growth factor receptor signaling pathway / endodermal cell differentiation / PECAM1 interactions / GRB2:SOS provides linkage to MAPK signaling for Integrins / TGF-beta receptor signaling activates SMADs / positive regulation of intracellular signal transduction / fibronectin binding / lamellipodium membrane / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / ECM proteoglycans / Integrin cell surface interactions / positive regulation of T cell migration / negative regulation of endothelial cell apoptotic process / vasculogenesis / specific granule membrane / voltage-gated calcium channel activity / coreceptor activity / cell adhesion molecule binding / phagocytic vesicle / cellular response to platelet-derived growth factor stimulus / ERK1 and ERK2 cascade / positive regulation of endothelial cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / Integrin signaling / embryo implantation / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of smooth muscle cell proliferation / positive regulation of endothelial cell migration
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 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 1. / EGF-like domain signature 2.
Similarity search - Domain/homology
Integrin beta-3 / Integrin alpha-V
Similarity search - Component
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.
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
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein 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 / 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: all / 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 FIELD
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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