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- PDB-9gl7: EGFR Exon20 insertion mutant NPG bound with (S)-3-((3-chloro-2-me... -

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基本情報

登録情報
データベース: PDB / ID: 9gl7
タイトルEGFR Exon20 insertion mutant NPG bound with (S)-3-((3-chloro-2-methoxyphenyl)amino)-2-(3-((tetrahydrofuran-2-yl)methoxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one
要素Epidermal growth factor receptor
キーワードTRANSFERASE / Kinase / Inhibitor
機能・相同性
機能・相同性情報


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / positive regulation of epithelial cell proliferation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway / neuron differentiation / cell morphogenesis / positive regulation of fibroblast proliferation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / Cargo recognition for clathrin-mediated endocytosis / cell junction / transmembrane signaling receptor activity / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / virus receptor activity / ATPase binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / endosome membrane
類似検索 - 分子機能
: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / : / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
類似検索 - ドメイン・相同性
: / Epidermal growth factor receptor
類似検索 - 構成要素
生物種Homo sapiens (ヒト)
手法X線回折 / シンクロトロン / 分子置換 / 解像度: 1.878 Å
データ登録者Hilbert, B.J. / Brooijmans, N. / Milgram, B.C. / Pagliarini, R.A.
資金援助1件
組織認可番号国
Not funded
引用ジャーナル: Clin.Cancer Res. / 年: 2025
タイトル: STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique Mutant Selectivity Across Human Cancer Models.
著者: Pagliarini, R.A. / Henderson, J.A. / Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Kryukov, G.V. / Ladd, B. / Martin, B.R. / Motiwala, H. / O'Hearn, ...著者: Pagliarini, R.A. / Henderson, J.A. / Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Kryukov, G.V. / Ladd, B. / Martin, B.R. / Motiwala, H. / O'Hearn, E. / Tsai, C.F. / Wang, W. / Bellier, J. / Boland, L. / Clark, S. / Hensley, E. / Hata, A.N. / Kuzmic, P. / Guzman-Perez, A. / Jackson, E.L. / Stuart, D.D.
履歴
登録2024年8月27日登録サイト: PDBE / 処理サイト: PDBE
改定 1.02025年5月14日Provider: repository / タイプ: Initial release
改定 1.12025年6月11日Group: Database references / カテゴリ: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
改定 1.22025年7月23日Group: Database references / カテゴリ: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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構造の表示

構造ビューア分子:
MolmilJmol/JSmol

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集合体

登録構造単位
A: Epidermal growth factor receptor
ヘテロ分子


分子量 (理論値)分子数
合計 (水以外)39,1472
ポリマ－38,6781
非ポリマー4691
水1,910106
1


  • 登録構造と同一
  • 登録者・ソフトウェアが定義した集合体
タイプ名称対称操作数
identity operation1_555x,y,z1
Buried area920 Å2
ΔGint-7 kcal/mol
Surface area14530 Å2
手法PISA
単位格子
Length a, b, c (Å)39.744, 105.781, 174.454
Angle α, β, γ (deg.)90, 90, 90
Int Tables number20
Space group name H-MC2221

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要素

#1: タンパク質 Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


分子量: 38677.609 Da / 分子数: 1 / 変異: V948R / 由来タイプ: 組換発現 / 詳細: D770_N771insNPG / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: EGFR, ERBB, ERBB1, HER1
発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ)
参照: UniProt: P00533, receptor protein-tyrosine kinase
#2: 化合物 ChemComp-A1IMS / 3-[(3-chloranyl-2-methoxy-phenyl)amino]-2-[3-[[(2S)-oxolan-2-yl]methoxy]pyridin-4-yl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one


分子量: 468.933 Da / 分子数: 1 / 由来タイプ: 合成 / 式: C24H25ClN4O4 / タイプ: SUBJECT OF INVESTIGATION
#3: 水 ChemComp-HOH / water


分子量: 18.015 Da / 分子数: 106 / 由来タイプ: 天然 / 式: H2O
研究の焦点であるリガンドがあるかY
Has protein modificationN

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実験情報

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実験

実験手法: X線回折 / 使用した結晶の数: 1

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試料調製

結晶マシュー密度: 2.37 Å3/Da / 溶媒含有率: 48.11 %
結晶化温度: 293 K / 手法: 蒸気拡散法, シッティングドロップ法 / pH: 8.5
詳細: 0.2 M Magnesium Chloride, 0.1 M TRIS-HCl pH 8.5, 20% w/v PEG 4000

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データ収集

回折平均測定温度: 100 K / Serial crystal experiment: N
放射光源由来: シンクロトロン / サイト: ESRF / ビームライン: MASSIF-1 / 波長: 0.965459 Å
検出器タイプ: DECTRIS PILATUS3 2M / 検出器: PIXEL / 日付: 2021年2月4日
放射プロトコル: SINGLE WAVELENGTH / 単色(M)・ラウエ(L): M / 散乱光タイプ: x-ray
放射波長波長: 0.965459 Å / 相対比: 1
反射解像度: 1.878→34.222 Å / Num. obs: 16502 / % possible obs: 82.1 % / 冗長度: 4.5 %
詳細: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last ...詳細: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last updated 2020-04-13: http://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Index/) and the actual quantities provided by MRFANA (https://github.com/githubgphl/MRFANA) from the autoPROC package (https://www.globalphasing.com/autoproc/). In general, the mmCIF categories here should provide items that are currently used in the PDB archive. If there are alternatives, the one recommended by the PDB developers has been selected. The distinction between *_all and *_obs quantities is not always clear: often only one version is actively used within the PDB archive (or is the one recommended by PDB developers). The intention of distinguishing between classes of reflections before and after some kind of observation criterion was applied, can in principle be useful - but such criteria change in various ways through the data processing procedure (rejection of overloaded or too partial reflections, outlier/misfit rejection during scaling etc) and there is no retrospect computation of data scaling/merging statistics for the reflections used in the final refinement (where another observation criterion might have been applied). Typical data processing will usually only provide one version of statistics at various stages and these are given in the recommended item here, irrespective of the "_all" and "_obs" connotation, see e.g. the use of _reflns.pdbx_Rmerge_I_obs, _reflns.pdbx_Rrim_I_all and _reflns.pdbx_Rpim_I_all. Please note that all statistics related to "merged intensities" (or "merging") are based on inverse-variance weighting of the individual measurements making up a symmetry-unique reflection. This is standard for several decades now, even if some of the dictionary definitions seem to suggest that a simple "mean" or "average" intensity is being used instead. R-values are always given for all symmetry-equivalent reflections following Friedel's law, i.e. Bijvoet pairs are not treated separately (since we want to describe the overall mean intensity and not the mean I(+) and I(-) here). The Rrim metric is identical to the Rmeas R-value and only differs in name. _reflns.pdbx_number_measured_all is the number of measured intensities just before the final merging step (at which point no additional rejection takes place). _reflns.number_obs is the number of symmetry-unique observations, i.e. the result of merging those measurements via inverse-variance weighting. _reflns.pdbx_netI_over_sigmaI is based on the merged intensities (_reflns.number_obs) as expected. _reflns.pdbx_redundancy is synonymous with "multiplicity". The per-shell item _reflns_shell.number_measured_all corresponds to the overall value _reflns.pdbx_number_measured_all. The per-shell item _reflns_shell.number_unique_all corresponds to the overall value _reflns.number_obs. The per-shell item _reflns_shell.percent_possible_all corresponds to the overall value _reflns.percent_possible_obs. The per-shell item _reflns_shell.meanI_over_sigI_obs corresponds to the overall value given as _reflns.pdbx_netI_over_sigmaI. But be aware of the incorrect definition of the former in the current dictionary!
CC1/2: 0.944 / Rmerge(I) obs: 0.2739 / Rpim(I) all: 0.1672 / Rrim(I) all: 0.3233 / Net I/σ(I): 6.76 / Num. measured all: 74289
反射 シェル
解像度 (Å)冗長度 (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
5.05-34.2223.860.114313.263596359164916490.9810.07290.136796.9
3.973-5.054.060.177712.2366976697165016500.9350.11620.213996.8
3.46-3.9734.240.259310.3870067006165216520.8760.16280.308397.5
3.118-3.463.820.35717.8363076307165016500.8040.22860.427191
2.837-3.1174.410.40356.8472727272165016500.7890.23340.469375.4
2.627-2.8374.590.61415.3775717571165016500.6510.35340.713571.3
2.45-2.6274.710.95444.0977777777165016500.4610.55571.11272.4
2.281-2.454.641.04043.4376567656165116510.3010.61791.219771.1
2.117-2.2814.841.1582.5179827982165016500.4040.63781.329984.9
1.878-2.1175.861.49581.7796629662165016500.4770.70331.657576.4

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解析

ソフトウェア
名称バージョン分類
autoPROC1.1.7 20201211data processing
XDSJun 1, 2017データ削減
Aimless0.7.4データスケーリング
STARANISO2.3.54データスケーリング
PHASER位相決定
BUSTER2.11.8精密化
精密化構造決定の手法: 分子置換 / 解像度: 1.878→34.22 Å / Cor.coef. Fo:Fc: 0.849 / Cor.coef. Fo:Fc free: 0.843 / 交差検証法: THROUGHOUT / SU R Blow DPI: 0.409 / SU Rfree Blow DPI: 0.261
Rfactor反射数%反射Selection details
Rfree0.2869 794 -RANDOM
Rwork0.2683 ---
obs0.2693 16502 53.9 %-
原子変位パラメータBiso mean: 46.26 Å2
Baniso -1Baniso -2Baniso -3
1--13.353 Å20 Å20 Å2
2---3.0164 Å20 Å2
3---16.3693 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
精密化ステップサイクル: LAST / 解像度: 1.878→34.22 Å
タンパク質核酸リガンド溶媒全体
原子数2411 0 33 106 2550
拘束条件
Refine-IDタイプDev ideal数Restraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0085008HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.979090HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1490SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes778HARMONIC5
X-RAY DIFFRACTIONt_it2525HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion321SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4107SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.88
X-RAY DIFFRACTIONt_other_torsion14.6
LS精密化 シェル解像度: 1.88→1.98 Å
Rfactor反射数%反射
Rfree0.3168 17 -
Rwork0.2773 --
obs0.2791 424 9.35 %
精密化 TLSOrigin x: 2.1618 Å / Origin y: 14.4604 Å / Origin z: -19.4314 Å
111213212223313233
T-0.304 Å20.0079 Å2-0.0279 Å2--0.1146 Å20.0177 Å2--0.2949 Å2
L0.258 °2-0.4042 °20.0796 °2-0.4722 °2-0.1734 °2--3.1974 °2
S-0.1353 Å °0.1822 Å °0.0302 Å °0.1822 Å °0.0208 Å °0.1049 Å °0.0302 Å °0.1049 Å °0.1145 Å °
精密化 TLSグループ
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A702 - 1019
2X-RAY DIFFRACTION1{ A|* }A2001

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