+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8ils | |||||||||||||||||||||||||||||||||||||||
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タイトル | Cryo-EM structure of PI3Kalpha in complex with compound 17 | |||||||||||||||||||||||||||||||||||||||
要素 |
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キーワード | STRUCTURAL PROTEIN / Phosphoinositide 3-kinase / drug target / ligand / binding pocket / chemical scaffold | |||||||||||||||||||||||||||||||||||||||
機能・相同性 | 機能・相同性情報 perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling / cellular response to hydrostatic pressure / positive regulation of focal adhesion disassembly / phosphatidylinositol 3-kinase activator activity / autosome genomic imprinting / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulatory subunit binding / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / cis-Golgi network / ErbB-3 class receptor binding / phosphatidylinositol 3-kinase complex, class IB / kinase activator activity / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOF GTPase cycle / regulation of cellular respiration / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / positive regulation of endoplasmic reticulum unfolded protein response / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex / Nephrin family interactions / relaxation of cardiac muscle / anoikis / Signaling by LTK in cancer / positive regulation of leukocyte migration / RND1 GTPase cycle / Costimulation by the CD28 family / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / Signaling by LTK / RND2 GTPase cycle / MET activates PI3K/AKT signaling / phosphatidylinositol-4,5-bisphosphate 3-kinase / PI3K/AKT activation / RND3 GTPase cycle / positive regulation of filopodium assembly / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / growth hormone receptor signaling pathway / RHOB GTPase cycle / negative regulation of stress fiber assembly / natural killer cell mediated cytotoxicity / phosphatidylinositol-3-phosphate biosynthetic process / insulin binding / RHOV GTPase cycle / 1-phosphatidylinositol-3-kinase activity / negative regulation of cell-matrix adhesion / Signaling by ALK / negative regulation of macroautophagy / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR2 / protein kinase activator activity / PI-3K cascade:FGFR4 / response to dexamethasone / RHOC GTPase cycle / RHOJ GTPase cycle / PI-3K cascade:FGFR1 / intracellular glucose homeostasis / negative regulation of osteoclast differentiation / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / CD28 dependent PI3K/Akt signaling / phosphatidylinositol phosphate biosynthetic process / CDC42 GTPase cycle / RHOU GTPase cycle / T cell differentiation / PI3K events in ERBB2 signaling / intercalated disc / negative regulation of anoikis / RET signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / RHOG GTPase cycle / extrinsic apoptotic signaling pathway via death domain receptors / RHOA GTPase cycle / regulation of multicellular organism growth / PI3K Cascade / endothelial cell migration / positive regulation of TOR signaling 類似検索 - 分子機能 | |||||||||||||||||||||||||||||||||||||||
生物種 | Homo sapiens (ヒト) | |||||||||||||||||||||||||||||||||||||||
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: 3.1 Å | |||||||||||||||||||||||||||||||||||||||
データ登録者 | Zhou, Q. / Liu, X. / Neri, D. / Li, W. / Favalli, N. / Bassi, G. / Yang, S. / Yang, D. / Vogt, P.K. / Wang, M.-W. | |||||||||||||||||||||||||||||||||||||||
資金援助 | 中国, 米国, 12件
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引用 | ジャーナル: Proc Natl Acad Sci U S A / 年: 2023 タイトル: Structural insights into the interaction of three Y-shaped ligands with PI3Kα. 著者: Qingtong Zhou / Xiao Liu / Dario Neri / Wenxin Li / Nicholas Favalli / Gabriele Bassi / Su Yang / Dehua Yang / Peter K Vogt / Ming-Wei Wang / 要旨: Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently ...Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently on the market or under development have safety concerns due to a lack of selectivity. Therefore, other chemical scaffolds or unique mechanisms of catalytic kinase inhibition are needed. Here, we report the cryo-electron microscopy structures of wild-type PI3Kα, the dimer of p110α and p85α, in complex with three Y-shaped ligands [cpd16 (compound 16), cpd17 (compound 17), and cpd18 (compound 18)] of different affinities and no inhibitory effect on the kinase activity. Unlike ATP-competitive inhibitors, cpd17 adopts a Y-shaped conformation with one arm inserted into a binding pocket formed by R770 and W780 and the other arm lodged in the ATP-binding pocket at an angle that is different from that of the ATP phosphate tail. Such a special interaction induces a conformation of PI3Kα resembling that of the unliganded protein. These observations were confirmed with two isomers (cpd16 and cpd18). Further analysis of these Y-shaped ligands revealed the structural basis of differential binding affinities caused by stereo- or regiochemical modifications. Our results may offer a different direction toward the design of therapeutic agents against PI3Kα. | |||||||||||||||||||||||||||||||||||||||
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 | 8ils.cif.gz | 253.3 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8ils.ent.gz | 192.6 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8ils.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 | 8ils_validation.pdf.gz | 1.2 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8ils_full_validation.pdf.gz | 1.2 MB | 表示 | |
XML形式データ | 8ils_validation.xml.gz | 53 KB | 表示 | |
CIF形式データ | 8ils_validation.cif.gz | 77.7 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/il/8ils ftp://data.pdbj.org/pub/pdb/validation_reports/il/8ils | HTTPS FTP |
-関連構造データ
関連構造データ | 35545MC 8ilrC 8ilvC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-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: 127822.578 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: PIK3CA / 発現宿主: Trichoplusia ni (イラクサキンウワバ) 参照: UniProt: P42336, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase |
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#2: タンパク質 | 分子量: 83623.203 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: PIK3R1, GRB1 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: P27986 |
#3: 化合物 | ChemComp-7U5 / |
#4: 水 | ChemComp-HOH / |
研究の焦点であるリガンドがあるか | Y |
-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: Human PI3Kalpha in complex with compound 17 / タイプ: COMPLEX / Entity ID: #1-#2 / 由来: MULTIPLE SOURCES |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Trichoplusia ni (イラクサキンウワバ) / 株: Sf-9 |
緩衝液 | pH: 7.6 |
試料 | 濃度: 1 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: OTHER / 加速電圧: 300 kV / 照射モード: OTHER |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 1500 nm |
撮影 | 電子線照射量: 70 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
-解析
EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||
3次元再構成 | 解像度: 3.1 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 536916 / 対称性のタイプ: POINT | ||||||||||||
原子モデル構築 | プロトコル: FLEXIBLE FIT / Target criteria: Correlation coefficient | ||||||||||||
原子モデル構築 | PDB-ID: 7MYN Accession code: 7MYN / Source name: PDB / タイプ: experimental model |