+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-7011 | |||||||||
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タイトル | The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance | |||||||||
マップデータ | The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance | |||||||||
試料 |
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キーワード | alpha-V beta-3 integrin / LM609 / vitaxin / abegrin / SIGNALING PROTEIN | |||||||||
機能・相同性 | 機能・相同性情報 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 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) / Mus musculus (ハツカネズミ) | |||||||||
手法 | 単粒子再構成法 / ネガティブ染色法 / 解像度: 35.0 Å | |||||||||
データ登録者 | Borst AJ / James ZN | |||||||||
資金援助 | 米国, 2件
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引用 | ジャーナル: Structure / 年: 2017 タイトル: The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αβ Integrin via Steric Hindrance. 著者: Andrew J Borst / Zachary M James / William N Zagotta / Mark Ginsberg / Felix A Rey / Frank DiMaio / Marija Backovic / David Veesler / 要旨: 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. | |||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_7011.map.gz | 2.5 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-7011-v30.xml emd-7011.xml | 16.2 KB 16.2 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_7011.png | 23.9 KB | ||
Filedesc metadata | emd-7011.cif.gz | 6.9 KB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-7011 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-7011 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_7011_validation.pdf.gz | 346.3 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_7011_full_validation.pdf.gz | 345.9 KB | 表示 | |
XML形式データ | emd_7011_validation.xml.gz | 5.8 KB | 表示 | |
CIF形式データ | emd_7011_validation.cif.gz | 6.5 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-7011 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-7011 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_7011.map.gz / 形式: CCP4 / 大きさ: 11.4 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 3.2054 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-試料の構成要素
-全体 : Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
全体 | 名称: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609 |
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要素 |
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-超分子 #1: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
超分子 | 名称: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 230 KDa |
-分子 #1: Integrin alpha-V
分子 | 名称: Integrin alpha-V / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 105.894188 KDa |
組換発現 | 生物種: Drosophila melanogaster (キイロショウジョウバエ) |
配列 | 文字列: FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKCD WSSTRRCQPI EFDATGNRDY AKDDPLEFK SHQWFGASVR SKQDKILACA PLYHWRTEMK QEREPVGTCF LQDGTKTVEY APCRSQDIDA DGQGFCQGGF S IDFTKADR ...文字列: 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 |
-分子 #2: Integrin beta-3
分子 | 名称: Integrin beta-3 / タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 76.523125 KDa |
組換発現 | 生物種: Drosophila melanogaster (キイロショウジョウバエ) |
配列 | 文字列: GPNICTTRGV SSCQQCLAVS PMCAWCSDEA LPLGSPRCDL KENLLKDNCA PESIEFPVSE ARVLEDRPLS DKGSGDSSQV TQVSPQRIA LRLRPDDSKN FSIQVRQVED YPVDIYYLMD LSYSMKDDLW SIQNLGTKLA TQMRKLTSNL RIGFGAFVDK P VSPYMYIS ...文字列: 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 |
-分子 #3: LM609 Fab heavy chain
分子 | 名称: LM609 Fab heavy chain / タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Mus musculus (ハツカネズミ) |
分子量 | 理論値: 27.2231 KDa |
組換発現 | 生物種: Drosophila melanogaster (キイロショウジョウバエ) |
配列 | 文字列: EVQLEESGGG LVKPGGSLKL SCAASGFAFS SYDMSWVRQI PEKRLEWVAK VSSGGGSTYY LDTVQGRFTI SRDNAKNTLY LQMSSLNSE DTAMYYCARH NYGSFAYWGQ GTLVTVSAAK TTPPSVYPLA PGSAAQTNSM VTLGCLVKGY FPEPVTVTWN S GSLSSGVH ...文字列: 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 |
-分子 #4: LM609 Fab light chain
分子 | 名称: LM609 Fab light chain / タイプ: protein_or_peptide / ID: 4 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Mus musculus (ハツカネズミ) |
分子量 | 理論値: 23.628977 KDa |
組換発現 | 生物種: Drosophila melanogaster (キイロショウジョウバエ) |
配列 | 文字列: ELVMTQTPAT LSVTPGDSVS LSCRASQSIS NHLHWYQQKS HESPRLLIKY ASQSISGIPS RFSGSGSGTD FTLSINSVET EDFGMYFCQ QSNSWPHTFG GGTKLEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...文字列: ELVMTQTPAT LSVTPGDSVS LSCRASQSIS NHLHWYQQKS HESPRLLIKY ASQSISGIPS RFSGSGSGTD FTLSINSVET EDFGMYFCQ QSNSWPHTFG GGTKLEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC |
-実験情報
-構造解析
手法 | ネガティブ染色法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 8 |
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染色 | タイプ: NEGATIVE / 材質: Uranyl formate |
グリッド | モデル: C-flat 2/0.5 / 材質: COPPER / メッシュ: 400 / 支持フィルム - 材質: CARBON / 支持フィルム - トポロジー: CONTINUOUS / 前処理 - タイプ: GLOW DISCHARGE |
-電子顕微鏡法
顕微鏡 | FEI TECNAI 12 |
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撮影 | フィルム・検出器のモデル: GATAN ULTRASCAN 4000 (4k x 4k) 平均電子線量: 30.0 e/Å2 |
電子線 | 加速電圧: 120 kV / 電子線源: LAB6 |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD |
-画像解析
初期モデル | モデルのタイプ: RANDOM CONICAL TILT |
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最終 再構成 | 想定した対称性 - 点群: C1 (非対称) / 解像度のタイプ: BY AUTHOR / 解像度: 35.0 Å / 解像度の算出法: FSC 0.5 CUT-OFF / 使用した粒子像数: 650 |
初期 角度割当 | タイプ: NOT APPLICABLE |
最終 角度割当 | タイプ: NOT APPLICABLE |
-原子モデル構築 1
精密化 | 空間: REAL / プロトコル: FLEXIBLE FIT |
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得られたモデル | PDB-6avq: |