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- EMDB-7013: Human alpha-V beta-3 Integrin (open conformation) in complex with... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-7013 | |||||||||
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Title | Human alpha-V beta-3 Integrin (open conformation) in complex with the therapeutic antibody LM609 | |||||||||
![]() | Human alpha-V beta-3 Integrin (open conformation) in complex with the therapeutic antibody LM609 | |||||||||
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![]() | alpha-V beta-3 integrin / LM609 / vitaxin / abegrin / SIGNALING PROTEIN | |||||||||
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 | single particle reconstruction / negative staining / Resolution: 35.0 Å | |||||||||
![]() | Borst AJ / James ZN | |||||||||
![]() | ![]() 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 | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 2.5 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.4 KB 15.4 KB | Display Display | ![]() |
Images | ![]() | 24.3 KB | ||
Filedesc metadata | ![]() | 6.7 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6avuMC ![]() 7011C ![]() 7012C ![]() 5opyC ![]() 6avqC ![]() 6avrC C: citing same article ( M: atomic model generated by this map |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Human alpha-V beta-3 Integrin (open conformation) in complex with the therapeutic antibody LM609 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 3.2054 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
Entire | Name: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609 |
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Components |
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-Supramolecule #1: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
Supramolecule | Name: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609 type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 230 KDa |
-Macromolecule #1: Integrin alpha-V
Macromolecule | Name: Integrin alpha-V / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 105.894188 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKCD WSSTRRCQPI EFDATGNRDY AKDDPLEFK SHQWFGASVR SKQDKILACA PLYHWRTEMK QEREPVGTCF LQDGTKTVEY APCRSQDIDA DGQGFCQGGF S IDFTKADR ...String: FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKCD WSSTRRCQPI EFDATGNRDY AKDDPLEFK SHQWFGASVR SKQDKILACA PLYHWRTEMK QEREPVGTCF LQDGTKTVEY APCRSQDIDA DGQGFCQGGF S IDFTKADR VLLGGPGSFY WQGQLISDQV AEIVSKYDPN VYSIKYNNQL ATRTAQAIFD DSYLGYSVAV GDFNGDGIDD FV SGVPRAA RTLGMVYIYD GKNMSSLYNF TGEQMAAYFG FSVAATDING DDYADVFIGA PLFMDRGSDG KLQEVGQVSV SLQ RASGDF QTTKLNGFEV FARFGSAIAP LGDLDQDGFN DIAIAAPYGG EDKKGIVYIF NGRSTGLNAV PSQILEGQWA ARSM PPSFG YSMKGATDID KNGYPDLIVG AFGVDRAILY RARPVITVNA GLEVYPSILN QDNKTCSLPG TALKVSCFNV RFCLK ADGK GVLPRKLNFQ VELLLDKLKQ KGAIRRALFL YSRSPSHSKN MTISRGGLMQ CEELIAYLRD ESEFRDKLTP ITIFME YRL DYRTAADTTG LQPILNQFTP ANISRQAHIL LDCGEDNVCK PKLEVSVDSD QKKIYIGDDN PLTLIVKAQN QGEGAYE AE LIVSIPLQAD FIGVVRNNEA LARLSCAFKT ENQTRQVVCD LGNPMKAGTQ LLAGLRFSVH QQSEMDTSVK FDLQIQSS N LFDKVSPVVS HKVDLAVLAA VEIRGVSSPD HIFLPIPNWE HKENPETEED VGPVVQHIYE LRNNGPSSFS KAMLHLQWP YKYNNNTLLY ILHYDIDGPM NCTSDMEINP LRIKISSLQT TEKNDTVAGQ GERDHLITKR DLALSEGDIH TLGCGVAQCL KIVCQVGRL DRGKSAILYV KSLLWTETFM NKENQNHSYS LKSSASFNVI EFPYKNLPIE DITNSTLVTT NVTWGIQP UniProtKB: Integrin alpha-V |
-Macromolecule #2: Integrin beta-3
Macromolecule | Name: Integrin beta-3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 76.523125 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: GPNICTTRGV SSCQQCLAVS PMCAWCSDEA LPLGSPRCDL KENLLKDNCA PESIEFPVSE ARVLEDRPLS DKGSGDSSQV TQVSPQRIA LRLRPDDSKN FSIQVRQVED YPVDIYYLMD LSYSMKDDLW SIQNLGTKLA TQMRKLTSNL RIGFGAFVDK P VSPYMYIS ...String: GPNICTTRGV SSCQQCLAVS PMCAWCSDEA LPLGSPRCDL KENLLKDNCA PESIEFPVSE ARVLEDRPLS DKGSGDSSQV TQVSPQRIA LRLRPDDSKN FSIQVRQVED YPVDIYYLMD LSYSMKDDLW SIQNLGTKLA TQMRKLTSNL RIGFGAFVDK P VSPYMYIS PPEALENPCY DMKTTCLPMF GYKHVLTLTD QVTRFNEEVK KQSVSRNRDA PEGGFDAIMQ ATVCDEKIGW RN DASHLLV FTTDAKTHIA LDGRLAGIVQ PNDGQCHVGS DNHYSASTTM DYPSLGLMTE KLSQKNINLI FAVTENVVNL YQN YSELIP GTTVGVLSMD SSNVLQLIVD AYGKIRSKVE LEVRDLPEEL SLSFNATCLN NEVIPGLKSC MGLKIGDTVS FSIE AKVRG CPQEKEKSFT IKPVGFKDSL IVQVTFDCDC ACQAQAEPNS HRCNNGNGTF ECGVCRCGPG WLGSQCECSE EDYRP SQQD ECSPREGQPV CSQRGECLCG QCVCHSSDFG KITGKYCECD DFSCVRYKGE MCSGHGQCSC GDCLCDSDWT GYYCNC TTR TDTCMSSNGL LCSGRGKCEC GSCVCIQPGS YGDTCEKCPT CPDACTFKKE CVECKKFDRG ALHDENTCNR YCRDEIE SV KELKDTGKDA VNCTYKNEDD CVVRFQYYED SSGKSILYVV EEPECPKGPD UniProtKB: Integrin beta-3 |
-Macromolecule #3: Fab LM609 heavy chain
Macromolecule | Name: Fab LM609 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 27.2231 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: EVQLEESGGG LVKPGGSLKL SCAASGFAFS SYDMSWVRQI PEKRLEWVAK VSSGGGSTYY LDTVQGRFTI SRDNAKNTLY LQMSSLNSE DTAMYYCARH NYGSFAYWGQ GTLVTVSAAK TTPPSVYPLA PGSAAQTNSM VTLGCLVKGY FPEPVTVTWN S GSLSSGVH ...String: EVQLEESGGG LVKPGGSLKL SCAASGFAFS SYDMSWVRQI PEKRLEWVAK VSSGGGSTYY LDTVQGRFTI SRDNAKNTLY LQMSSLNSE DTAMYYCARH NYGSFAYWGQ GTLVTVSAAK TTPPSVYPLA PGSAAQTNSM VTLGCLVKGY FPEPVTVTWN S GSLSSGVH TFPAVLQSDL YTLSSSVTVP SSTWPSETVT CNVAHPASST KVDKKIVPRD CGASDDDDKA GWSHPQFEKG GG SGGGSGG GSWSHPQFEK |
-Macromolecule #4: Fab LM609 light chain
Macromolecule | Name: Fab LM609 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 23.628977 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: ELVMTQTPAT LSVTPGDSVS LSCRASQSIS NHLHWYQQKS HESPRLLIKY ASQSISGIPS RFSGSGSGTD FTLSINSVET EDFGMYFCQ QSNSWPHTFG GGTKLEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...String: ELVMTQTPAT LSVTPGDSVS LSCRASQSIS NHLHWYQQKS HESPRLLIKY ASQSISGIPS RFSGSGSGTD FTLSINSVET EDFGMYFCQ QSNSWPHTFG GGTKLEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC |
-Experimental details
-Structure determination
Method | negative staining |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Staining | Type: NEGATIVE / Material: Uranyl formate |
Grid | Model: C-flat 2/0.5 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE |
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Electron microscopy
Microscope | FEI TECNAI 12 |
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Image recording | Film or detector model: GATAN ULTRASCAN 4000 (4k x 4k) / Average electron dose: 30.0 e/Å2 |
Electron beam | Acceleration voltage: 120 kV / Electron source: LAB6 |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
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Image processing
Startup model | Type of model: RANDOM CONICAL TILT |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 35.0 Å / Resolution method: FSC 0.5 CUT-OFF / Number images used: 650 |
Initial angle assignment | Type: NOT APPLICABLE |
Final angle assignment | Type: NOT APPLICABLE |
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: FLEXIBLE FIT |
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Output model | ![]() PDB-6avu: |