登録情報 データベース : EMDB / ID : EMD-35547 ダウンロードとリンクタイトル Cryo-EM structure of PI3Kalpha in complex with compound 18 マップデータ 詳細 試料複合体 : Human PI3Kalpha in complex with compound 18タンパク質・ペプチド : Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoformタンパク質・ペプチド : Phosphatidylinositol 3-kinase regulatory subunit alphaリガンド : N-[(2R)-1-(ethylamino)-1-oxidanylidene-3-[3-(2-quinoxalin-6-ylethynyl)phenyl]propan-2-yl]-2,3-dimethyl-quinoxaline-6-carboxamideリガンド : water 詳細 キーワード Phosphoinositide 3-kinase / drug target / ligand / binding pocket / chemical scaffold / STRUCTURAL PROTEIN機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / phosphatidylinositol kinase activity / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response ... perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / phosphatidylinositol kinase activity / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / IRS-mediated signalling / response to L-leucine / phosphatidylinositol 3-kinase activator activity / T follicular helper cell differentiation / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / phosphatidylinositol 3-kinase regulatory subunit binding / myeloid leukocyte migration / neurotrophin TRKA receptor binding / cellular response to hydrostatic pressure / positive regulation of focal adhesion disassembly / autosome genomic imprinting / Activated NTRK2 signals through PI3K / cis-Golgi network / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / transmembrane receptor protein tyrosine kinase adaptor activity / phosphatidylinositol 3-kinase complex, class IB / ErbB-3 class receptor binding / phosphatidylinositol 3-kinase complex / negative regulation of stress fiber assembly / TORC2 signaling / Signaling by cytosolic FGFR1 fusion mutants / Co-stimulation by ICOS / positive regulation of protein localization to membrane / vasculature development / RHOD GTPase cycle / regulation of cellular respiration / Nephrin family interactions / RHOF GTPase cycle / Signaling by LTK / Signaling by LTK in cancer / 1-phosphatidylinositol-4-phosphate 3-kinase activity / anoikis / kinase activator activity / relaxation of cardiac muscle / positive regulation of leukocyte migration / MET activates PI3K/AKT signaling / RND1 GTPase cycle / phosphatidylinositol 3-kinase complex, class IA / RND2 GTPase cycle / PI3K/AKT activation / positive regulation of filopodium assembly / phosphatidylinositol-4,5-bisphosphate 3-kinase / RND3 GTPase cycle / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol 3-kinase / growth hormone receptor signaling pathway / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by ALK / cardiac muscle cell contraction / 1-phosphatidylinositol-3-kinase activity / RHOV GTPase cycle / vascular endothelial growth factor signaling pathway / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / RHOB GTPase cycle / natural killer cell mediated cytotoxicity / GP1b-IX-V activation signalling / response to dexamethasone / PI-3K cascade:FGFR2 / negative regulation of macroautophagy / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / negative regulation of osteoclast differentiation / phosphatidylinositol phosphate biosynthetic process / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / RHOU GTPase cycle / RET signaling / CDC42 GTPase cycle / negative regulation of anoikis / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K events in ERBB2 signaling / T cell differentiation / PI3K Cascade / RHOG GTPase cycle / intercalated disc / negative regulation of cell-matrix adhesion / extrinsic apoptotic signaling pathway via death domain receptors / Role of LAT2/NTAL/LAB on calcium mobilization / regulation of multicellular organism growth / CD28 dependent PI3K/Akt signaling / RHOA GTPase cycle / RAC2 GTPase cycle / RAC3 GTPase cycle 類似検索 - 分子機能 PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain ... PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / Rho GTPase activation protein / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / C2 domain superfamily / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily 類似検索 - ドメイン・相同性 Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform 類似検索 - 構成要素生物種 Homo sapiens (ヒト)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.19 Å 詳細 データ登録者Zhou Q / Liu X / Neri D / Li W / Favalli N / Bassi G / Yang S / Yang D / Vogt PK / Wang M-W 資金援助 中国, 米国, 12件 詳細 詳細を隠すOrganization Grant number 国 National Natural Science Foundation of China (NSFC) 81872915 中国 National Natural Science Foundation of China (NSFC) 82073904 中国 National Natural Science Foundation of China (NSFC) 82121005 中国 National Natural Science Foundation of China (NSFC) 81973373 中国 National Natural Science Foundation of China (NSFC) 21704064 中国 Other government 2018ZX09735-001 Other government 2018ZX09711002-002-005 Other government 2021ZD0203400 Other government 2018YFA0507000 Other government ZDKJ2021028 Other government NNCAS-2017-1-CC National Institutes of Health/National Cancer Institute (NIH/NCI) R35 CA197582 米国
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 登録 2023年3月4日 - ヘッダ(付随情報) 公開 2023年9月6日 - マップ公開 2023年9月6日 - 更新 2023年9月6日 - 現状 2023年9月6日 処理サイト : PDBc / 状態 : 公開
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