+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 6avr | ||||||
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タイトル | Human alpha-V beta-3 Integrin (intermediate conformation) in complex with the therapeutic antibody LM609 | ||||||
要素 |
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キーワード | SIGNALING PROTEIN / alpha-V beta-3 integrin / LM609 / vitaxin / abegrin | ||||||
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 | 電子顕微鏡法 / 単粒子再構成法 / ネガティブ染色法 / 解像度: 35 Å | ||||||
データ登録者 | Borst, A.J. / James, Z.N. / Zagotta, W.N. / Ginsberg, M. / Rey, F.A. / DiMaio, F. / Backovic, M. / Veesler, D. | ||||||
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 | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 6avr.cif.gz | 307.3 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb6avr.ent.gz | 209.9 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 6avr.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 6avr_validation.pdf.gz | 668.1 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 6avr_full_validation.pdf.gz | 669.2 KB | 表示 | |
XML形式データ | 6avr_validation.xml.gz | 43.8 KB | 表示 | |
CIF形式データ | 6avr_validation.cif.gz | 73.4 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/av/6avr ftp://data.pdbj.org/pub/pdb/validation_reports/av/6avr | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
#1: タンパク質 | 分子量: 105894.188 Da / 分子数: 1 / 断片: UNP residues 31-987 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: ITGAV, MSK8, VNRA, VTNR 発現宿主: Drosophila melanogaster (キイロショウジョウバエ) 参照: UniProt: P06756 |
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#2: タンパク質 | 分子量: 76523.125 Da / 分子数: 1 / 断片: UNP residues 27-718 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: ITGB3, GP3A 発現宿主: Drosophila melanogaster (キイロショウジョウバエ) 参照: UniProt: P05106 |
#3: 抗体 | 分子量: 27223.100 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Mus musculus (ハツカネズミ) 発現宿主: Drosophila melanogaster (キイロショウジョウバエ) |
#4: 抗体 | 分子量: 23628.977 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Mus musculus (ハツカネズミ) 発現宿主: Drosophila melanogaster (キイロショウジョウバエ) |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
-試料調製
構成要素 | 名称: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609 タイプ: COMPLEX / Entity ID: all / 由来: RECOMBINANT |
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分子量 | 値: 0.23 MDa / 実験値: NO |
由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Drosophila melanogaster (キイロショウジョウバエ) |
緩衝液 | pH: 8 |
試料 | 包埋: NO / シャドウイング: NO / 染色: YES / 凍結: NO |
染色 | タイプ: NEGATIVE / 染色剤: Uranyl formate |
試料支持 | グリッドの材料: COPPER / グリッドのサイズ: 400 divisions/in. / グリッドのタイプ: C-flat 2/0.5 |
-電子顕微鏡撮影
顕微鏡 | モデル: FEI TECNAI 12 |
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電子銃 | 電子線源: LAB6 / 加速電圧: 120 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 30 e/Å2 フィルム・検出器のモデル: GATAN ULTRASCAN 4000 (4k x 4k) |
-解析
EMソフトウェア |
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CTF補正 | タイプ: NONE | |||||||||
3次元再構成 | 解像度: 35 Å / 解像度の算出法: FSC 0.5 CUT-OFF / 粒子像の数: 650 / 対称性のタイプ: POINT | |||||||||
原子モデル構築 | プロトコル: FLEXIBLE FIT / 空間: REAL |