+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8tcg | ||||||||||||||||||
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タイトル | Integrin alpha-v beta-6 in complex with minibinder B6_BP_dslf | ||||||||||||||||||
要素 |
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キーワード | DE NOVO PROTEIN / Complex / heterodimer / signaling / ECM-binding | ||||||||||||||||||
機能・相同性 | 機能・相同性情報 Langerhans cell differentiation / integrin alphav-beta6 complex / integrin alphav-beta8 complex / hard palate development / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / : / opsonin binding / integrin alphav-beta1 complex ...Langerhans cell differentiation / integrin alphav-beta6 complex / integrin alphav-beta8 complex / hard palate development / 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) / enamel mineralization / extracellular matrix protein binding / bronchiole development / Laminin interactions / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / alphav-beta3 integrin-PKCalpha complex / entry into host cell by a symbiont-containing vacuole / alphav-beta3 integrin-HMGB1 complex / phospholipid homeostasis / negative regulation of lipid transport / negative regulation of low-density lipoprotein receptor activity / regulation of phagocytosis / Elastic fibre formation / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / surfactant homeostasis / filopodium membrane / positive regulation of small GTPase mediated signal transduction / extracellular matrix binding / apolipoprotein A-I-mediated signaling pathway / apoptotic cell clearance / wound healing, spreading of epidermal cells / heterotypic cell-cell adhesion / integrin complex / Molecules associated with elastic fibres / positive regulation of intracellular signal transduction / skin development / microvillus membrane / negative chemotaxis / cell adhesion mediated by integrin / Syndecan interactions / lung alveolus development / cell-substrate adhesion / endodermal cell differentiation / positive regulation of osteoblast proliferation / TGF-beta receptor signaling activates SMADs / PECAM1 interactions / lamellipodium membrane / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / fibronectin binding / positive regulation of cell adhesion / ECM proteoglycans / voltage-gated calcium channel activity / vasculogenesis / Integrin cell surface interactions / coreceptor activity / specific granule membrane / extrinsic apoptotic signaling pathway in absence of ligand / ERK1 and ERK2 cascade / phagocytic vesicle / substrate adhesion-dependent cell spreading / transforming growth factor beta receptor signaling pathway / cell-matrix adhesion / Signal transduction by L1 / molecular function activator activity / integrin-mediated signaling pathway / cellular response to ionizing radiation / negative regulation of extrinsic apoptotic signaling pathway / calcium ion transmembrane transport / protein kinase C binding / wound healing / response to virus / bone development / cell morphogenesis / ruffle membrane / VEGFA-VEGFR2 Pathway / cell-cell adhesion / cell migration / integrin binding / cell junction / virus receptor activity / positive regulation of cytosolic calcium ion concentration / angiogenesis / protease binding / receptor complex / cell adhesion / positive regulation of cell migration / inflammatory response / symbiont entry into host cell / immune response / external side of plasma membrane / focal adhesion / centrosome / positive regulation of cell population proliferation / Neutrophil degranulation / cell surface / extracellular exosome 類似検索 - 分子機能 | ||||||||||||||||||
生物種 | Homo sapiens (ヒト) synthetic construct (人工物) | ||||||||||||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.4 Å | ||||||||||||||||||
データ登録者 | Campbell, M.G. / Fernandez, A. / Roy, A. / Kraft, J. / Baker, D. | ||||||||||||||||||
資金援助 | 米国, 5件
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引用 | ジャーナル: Nat Commun / 年: 2023 タイトル: De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8. 著者: Anindya Roy / Lei Shi / Ashley Chang / Xianchi Dong / Andres Fernandez / John C Kraft / Jing Li / Viet Q Le / Rebecca Viazzo Winegar / Gerald Maxwell Cherf / Dean Slocum / P Daniel Poulson / ...著者: Anindya Roy / Lei Shi / Ashley Chang / Xianchi Dong / Andres Fernandez / John C Kraft / Jing Li / Viet Q Le / Rebecca Viazzo Winegar / Gerald Maxwell Cherf / Dean Slocum / P Daniel Poulson / Garrett E Casper / Mary L Vallecillo-Zúniga / Jonard Corpuz Valdoz / Marcos C Miranda / Hua Bai / Yakov Kipnis / Audrey Olshefsky / Tanu Priya / Lauren Carter / Rashmi Ravichandran / Cameron M Chow / Max R Johnson / Suna Cheng / McKaela Smith / Catherine Overed-Sayer / Donna K Finch / David Lowe / Asim K Bera / Gustavo Matute-Bello / Timothy P Birkland / Frank DiMaio / Ganesh Raghu / Jennifer R Cochran / Lance J Stewart / Melody G Campbell / Pam M Van Ry / Timothy Springer / David Baker / 要旨: The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between ...The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity. | ||||||||||||||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8tcg.cif.gz | 281.5 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8tcg.ent.gz | 227.3 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8tcg.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 | 8tcg_validation.pdf.gz | 1.4 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8tcg_full_validation.pdf.gz | 1.4 MB | 表示 | |
XML形式データ | 8tcg_validation.xml.gz | 34.7 KB | 表示 | |
CIF形式データ | 8tcg_validation.cif.gz | 49.7 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/tc/8tcg ftp://data.pdbj.org/pub/pdb/validation_reports/tc/8tcg | 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
-タンパク質 , 3種, 3分子 ABC
#1: タンパク質 | 分子量: 47898.004 Da / 分子数: 1 / 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: Cricetulus griseus (モンゴルキヌゲネズミ) 参照: UniProt: P06756 |
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#2: タンパク質 | 分子量: 26948.713 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: ITGB6 発現宿主: Cricetulus griseus (モンゴルキヌゲネズミ) 参照: UniProt: P18564 |
#3: タンパク質 | 分子量: 8415.737 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) synthetic construct (人工物) / 発現宿主: Escherichia coli (大腸菌) |
-糖 , 2種, 3分子
#4: 多糖 | alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose |
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#6: 糖 |
-非ポリマー , 2種, 7分子
#5: 化合物 | ChemComp-CA / #7: 化合物 | |
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-詳細
研究の焦点であるリガンドがあるか | N |
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-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: Ternary complex of integrin heterodimer (alpha-v beta-6) and the de novo minibinder protein B6_BP_dslf タイプ: COMPLEX 詳細: Integrin expressed in expiCHO cells, minibinder expressed in e. coli Entity ID: #1-#3 / 由来: RECOMBINANT |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Cricetulus griseus (モンゴルキヌゲネズミ) 株: expiCHO |
緩衝液 | pH: 7.4 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
試料支持 | グリッドの材料: GOLD |
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
顕微鏡 | モデル: TFS GLACIOS |
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電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 200 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1800 nm / 最小 デフォーカス(公称値): 1000 nm |
撮影 | 電子線照射量: 50 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
-解析
画像処理 | 詳細: Movies were collected in super resolution and gain corrected |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
3次元再構成 | 解像度: 3.4 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 124715 / 対称性のタイプ: POINT |