+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-43931 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
タイトル | CryoEM structure of activated CRAF/MEK/14-3-3 complex with NST-628 | |||||||||
マップデータ | ||||||||||
試料 |
| |||||||||
キーワード | Inhibitor / complex / SIGNALING PROTEIN / TRANSFERASE (転移酵素) | |||||||||
機能・相同性 | 機能・相同性情報 death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / intermediate filament cytoskeleton organization / placenta blood vessel development / regulation of axon regeneration / MAPキナーゼキナーゼ / labyrinthine layer development / type B pancreatic cell proliferation / MAP-kinase scaffold activity ...death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / intermediate filament cytoskeleton organization / placenta blood vessel development / regulation of axon regeneration / MAPキナーゼキナーゼ / labyrinthine layer development / type B pancreatic cell proliferation / MAP-kinase scaffold activity / cerebellar cortex formation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Signaling by MAP2K mutants / Rap1 signalling / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / regulation of Golgi inheritance / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / positive regulation of axonogenesis / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / GP1b-IX-V activation signalling / regulation of epidermal cell division / ERBB2-ERBB3 signaling pathway / protein kinase C inhibitor activity / protein kinase activator activity / positive regulation of epidermal cell differentiation / keratinocyte development / ケラチン / endodermal cell differentiation / regulation of cell differentiation / face development / MAPK3 (ERK1) activation / 仮足 / somatic stem cell population maintenance / Bergmann glial cell differentiation / MAP kinase kinase activity / thyroid gland development / neurotrophin TRK receptor signaling pathway / グルタチオン-S-トランスフェラーゼ / Uptake and function of anthrax toxins / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / glutathione transferase activity / extrinsic apoptotic signaling pathway via death domain receptors / phosphoserine residue binding / MAP kinase kinase kinase activity / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / establishment of skin barrier / negative regulation of protein-containing complex assembly / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Schwann cell development / type II interferon-mediated signaling pathway / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / RHO GTPases activate PKNs / keratinocyte differentiation / protein kinase A signaling / activation of adenylate cyclase activity / response to muscle stretch / ERK1 and ERK2 cascade / protein export from nucleus / 髄鞘 / negative regulation of innate immune response / protein serine/threonine/tyrosine kinase activity / protein sequestering activity / CD209 (DC-SIGN) signaling / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / insulin-like growth factor receptor signaling pathway / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / release of cytochrome c from mitochondria / positive regulation of protein export from nucleus / thymus development / Signal transduction by L1 / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / 運動性 / TP53 Regulates Metabolic Genes / RAF activation / negative regulation of protein kinase activity / Signaling by high-kinase activity BRAF mutants / wound healing / MAP2K and MAPK activation / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / neuron differentiation / positive regulation of protein serine/threonine kinase activity / Stimuli-sensing channels / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF 類似検索 - 分子機能 | |||||||||
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: 4.36 Å | |||||||||
データ登録者 | Quade B / Cohen SE / Huang X | |||||||||
資金援助 | 1件
| |||||||||
引用 | ジャーナル: Cancer Discov / 年: 2024 タイトル: The pan-RAF-MEK non degrading molecular glue NST-628 is a potent and brain penetrant inhibitor of the RAS-MAPK pathway with activity across diverse RAS- and RAF-driven cancers. 著者: Meagan B Ryan / Bradley Quade / Natasha Schenk / Zhong Fang / Marshall Zingg / Steven E Cohen / Brooke M Swalm / Chun Li / Aysegul Ozen / Chaoyang Ye / Maria Stella Ritorto / Xin Huang / ...著者: Meagan B Ryan / Bradley Quade / Natasha Schenk / Zhong Fang / Marshall Zingg / Steven E Cohen / Brooke M Swalm / Chun Li / Aysegul Ozen / Chaoyang Ye / Maria Stella Ritorto / Xin Huang / Arvin C Dar / Yongxin Han / Klaus P Hoeflich / Michael Hale / Margit Hagel / 要旨: Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents ...Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAFand prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies , NST-628 is positioned to make an impact clinically in an areas of unmet patient need. | |||||||||
履歴 |
|
-構造の表示
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_43931.map.gz | 2.3 MB | EMDBマップデータ形式 | |
---|---|---|---|---|
ヘッダ (付随情報) | emd-43931-v30.xml emd-43931.xml | 17.5 KB 17.5 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_43931.png | 48.2 KB | ||
Filedesc metadata | emd-43931.cif.gz | 6.6 KB | ||
その他 | emd_43931_half_map_1.map.gz emd_43931_half_map_2.map.gz | 23.4 MB 23.5 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-43931 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-43931 | HTTPS FTP |
-関連構造データ
関連構造データ | 9axaMC 9axcC 9axhC 9axmC 9axxC 9axyC 9ay7C 9ayaC M: このマップから作成された原子モデル C: 同じ文献を引用 (文献) |
---|---|
類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
---|---|
「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_43931.map.gz / 形式: CCP4 / 大きさ: 30.5 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
ボクセルのサイズ | X=Y=Z: 1.8105 Å | ||||||||||||||||||||
密度 |
| ||||||||||||||||||||
対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
|
-添付データ
-ハーフマップ: #2
ファイル | emd_43931_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
投影像・断面図 |
| ||||||||||||
密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_43931_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
投影像・断面図 |
| ||||||||||||
密度ヒストグラム |
-試料の構成要素
-全体 : CRAF/MEK/14-3-3 complex with NST-628
全体 | 名称: CRAF/MEK/14-3-3 complex with NST-628 |
---|---|
要素 |
|
-超分子 #1: CRAF/MEK/14-3-3 complex with NST-628
超分子 | 名称: CRAF/MEK/14-3-3 complex with NST-628 / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3 |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: GST26/CRAF chimera
分子 | 名称: GST26/CRAF chimera / タイプ: protein_or_peptide / ID: 1 / コピー数: 2 / 光学異性体: LEVO / EC番号: グルタチオン-S-トランスフェラーゼ |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 64.798465 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MSPILGYWKI KGLVQPTRLL LEYLEEKYEE HLYERDEGDK WRNKKFELGL EFPNLPYYID GDVKLTQSMA IIRYIADKHN MLGGCPKER AEISMLEGAV LDIRYGVSRI AYSKDFETLK VDFLSKLPEM LKMFEDRLCH KTYLNGDHVT HPDFMLYDAL D VVLYMDPM ...文字列: MSPILGYWKI KGLVQPTRLL LEYLEEKYEE HLYERDEGDK WRNKKFELGL EFPNLPYYID GDVKLTQSMA IIRYIADKHN MLGGCPKER AEISMLEGAV LDIRYGVSRI AYSKDFETLK VDFLSKLPEM LKMFEDRLCH KTYLNGDHVT HPDFMLYDAL D VVLYMDPM CLDAFPKLVC FKKRIEAIPQ IDKYLKSSKY IAWPLQGWQA TFGGGDHPPK SDSQPKTPVP AQRERAPVSG TQ EKNKIRP RGQRDSSDDW EIEASEVMLS TRIGSGSFGT VYKGKWHGDV AVKILKVVDP TPEQFQAFRN EVAVLRKTRH VNI LLFMGY MTKDNLAIVT QWCEGSSLYK HLHVQETKFQ MFQLIDIARQ TAQGMDYLHA KNIIHRDMKS NNIFLHEGLT VKIG DFGLA TVKSRWSGSQ QVEQPTGSVL WMAPEVIRMQ DNNPFSFQSD VYSYGIVLYE LMTGELPYSH INNRDQIIFM VGRGY ASPD LSKLYKNCPK AMKRLVADCV KKVKEERPLF PQILSSIELL QHSLPKINRS A(SEP)EPSLHRAA HTEDINACTL TT SPRLPVF UniProtKB: Glutathione S-transferase class-mu 26 kDa isozyme, RAF proto-oncogene serine/threonine-protein kinase |
-分子 #2: Dual specificity mitogen-activated protein kinase kinase 1
分子 | 名称: Dual specificity mitogen-activated protein kinase kinase 1 タイプ: protein_or_peptide / ID: 2 / コピー数: 2 / 光学異性体: LEVO / EC番号: MAPキナーゼキナーゼ |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 43.518988 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: GMPKKKPTPI QLNPAPDGSA VNGTSSAETN LEALQKKLEE LELDEQQRKR LEAFLTQKQK VGELKDDDFE KISELGAGNG GVVFKVSHK PSGLVMARKL IHLEIKPAIR NQIIRELQVL HECNSPYIVG FYGAFYSDGE ISICMEHMDG GSLDQVLKKA G RIPEQILG ...文字列: GMPKKKPTPI QLNPAPDGSA VNGTSSAETN LEALQKKLEE LELDEQQRKR LEAFLTQKQK VGELKDDDFE KISELGAGNG GVVFKVSHK PSGLVMARKL IHLEIKPAIR NQIIRELQVL HECNSPYIVG FYGAFYSDGE ISICMEHMDG GSLDQVLKKA G RIPEQILG KVSIAVIKGL TYLREKHKIM HRDVKPSNIL VNSRGEIKLC DFGVSGQLID AMANAFVGTR SYMSPERLQG TH YSVQSDI WSMGLSLVEM AVGRYPIPPP DAKELELMFG CQVEGDAAET PPRPRTPGRP LSSYGMDSRP PMAIFELLDY IVN EPPPKL PSGVFSLEFQ DFVNKCLIKN PAERADLKQL MVHAFIKRSD AEEVDFAGWL CSTIGLNQPS TPTHAAGV UniProtKB: Dual specificity mitogen-activated protein kinase kinase 1 |
-分子 #3: 14-3-3 protein sigma
分子 | 名称: 14-3-3 protein sigma / タイプ: protein_or_peptide / ID: 3 / コピー数: 2 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 27.807064 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MERASLIQKA KLAEQAERYE DMAAFMKGAV EKGEELSCEE RNLLSVAYKN VVGGQRAAWR VLSSIEQKSN EEGSEEKGPE VREYREKVE TELQGVCDTV LGLLDSHLIK EAGDAESRVF YLKMKGDYYR YLAEVATGDD KKRIIDSARS AYQEAMDISK K EMPPTNPI ...文字列: MERASLIQKA KLAEQAERYE DMAAFMKGAV EKGEELSCEE RNLLSVAYKN VVGGQRAAWR VLSSIEQKSN EEGSEEKGPE VREYREKVE TELQGVCDTV LGLLDSHLIK EAGDAESRVF YLKMKGDYYR YLAEVATGDD KKRIIDSARS AYQEAMDISK K EMPPTNPI RLGLALNFSV FHYEIANSPE EAISLAKTTF DEAMADLHTL SEDSYKDSTL IMQLLRDNLT LWTADNAGEE GG EAPQEPQ S UniProtKB: 14-3-3 protein sigma |
-分子 #4: N-[3-fluoro-4-({7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2-oxo-2H-1...
分子 | 名称: N-[3-fluoro-4-({7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2-oxo-2H-1-benzopyran-3-yl}methyl)pyridin-2-yl]-N'-methylsulfuric diamide タイプ: ligand / ID: 4 / コピー数: 2 / 式: A1AHE |
---|---|
分子量 | 理論値: 488.464 Da |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
---|---|
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: 7.5 |
---|---|
凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | TFS GLACIOS |
---|---|
電子線 | 加速電圧: 200 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELDBright-field microscopy / 最大 デフォーカス(公称値): 2.5 µm / 最小 デフォーカス(公称値): 1.0 µm |
撮影 | フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) 平均電子線量: 50.0 e/Å2 |
-画像解析
初期モデル | モデルのタイプ: EMDB MAP EMDB ID: |
---|---|
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 4.36 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 83248 |