[English] 日本語
Yorodumi
- PDB-7u98: EGFR(T790M/V948R) in complex with a macrocyclic inhibitor -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 7u98
TitleEGFR(T790M/V948R) in complex with a macrocyclic inhibitor
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / EGFR / kinase / macrocycle / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / basal plasma membrane / positive regulation of DNA repair / 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
Similarity search - Function
: / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-M1O / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.42 Å
AuthorsBeyett, T.S. / Eck, M.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5F32CA247198-02 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA116020-15 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Macrocyclization of Quinazoline-Based EGFR Inhibitors Leads to Exclusive Mutant Selectivity for EGFR L858R and Del19.
Authors: Amrhein, J.A. / Beyett, T.S. / Feng, W.W. / Kramer, A. / Weckesser, J. / Schaeffner, I.K. / Rana, J.K. / Janne, P.A. / Eck, M.J. / Knapp, S. / Hanke, T.
History
DepositionMar 10, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Dec 21, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,6988
Polymers150,8984
Non-polymers1,7994
Water00
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1742
Polymers37,7251
Non-polymers4501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1742
Polymers37,7251
Non-polymers4501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1742
Polymers37,7251
Non-polymers4501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1742
Polymers37,7251
Non-polymers4501
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.353, 100.923, 88.309
Angle α, β, γ (deg.)90.000, 102.170, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 702 through 859 or resid 877...
21(chain B and (resid 702 through 748 or resid 755...
31(chain C and (resid 702 through 859 or resid 877...
41(chain D and (resid 702 through 859 or resid 877...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ALAALAALAALA(chain A and (resid 702 through 859 or resid 877...AA702 - 85911 - 168
12PROPROLEULEU(chain A and (resid 702 through 859 or resid 877...AA877 - 907186 - 216
13THRTHRGLUGLU(chain A and (resid 702 through 859 or resid 877...AA909 - 1005218 - 314
14M1OM1OM1OM1O(chain A and (resid 702 through 859 or resid 877...AE1101
21ALAALAARGARG(chain B and (resid 702 through 748 or resid 755...BB702 - 74811 - 57
22ALAALAALAALA(chain B and (resid 702 through 748 or resid 755...BB755 - 85964 - 168
23PROPROLEULEU(chain B and (resid 702 through 748 or resid 755...BB877 - 907186 - 216
24THRTHRM1OM1O(chain B and (resid 702 through 748 or resid 755...BB - F909 - 1101218
31ALAALAALAALA(chain C and (resid 702 through 859 or resid 877...CC702 - 85911 - 168
32PROPROLEULEU(chain C and (resid 702 through 859 or resid 877...CC877 - 907186 - 216
33THRTHRGLUGLU(chain C and (resid 702 through 859 or resid 877...CC909 - 1005218 - 314
34M1OM1OM1OM1O(chain C and (resid 702 through 859 or resid 877...CG1101
41ALAALAALAALA(chain D and (resid 702 through 859 or resid 877...DD702 - 85911 - 168
42PROPROLEULEU(chain D and (resid 702 through 859 or resid 877...DD877 - 907186 - 216
43THRTHRGLUGLU(chain D and (resid 702 through 859 or resid 877...DD909 - 1005218 - 314
44M1OM1OM1OM1O(chain D and (resid 702 through 859 or resid 877...DH1101

-
Components

#1: Protein
Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37724.598 Da / Num. of mol.: 4 / Fragment: kinase domain, residues 695-1022 / Mutation: T790M, V948R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pTriEX / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-M1O / 19-chloro-18-fluoro-22-methoxy-8,9,11,12,14,15-hexahydro-21H-4,6-ethenopyrimido[5,4-m][1,4,7,10,15]benzotetraoxazacycloheptadecine


Mass: 449.860 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H21ClFN3O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalMosaicity: 0.444 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M Bis-Tris pH 5.5, 30% (w/v) PEG 3350

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 23, 2021
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 3.41→86.32 Å / Num. obs: 16531 / % possible obs: 98.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 82.79 Å2 / Rpim(I) all: 0.109 / Rrim(I) all: 0.204 / Net I/σ(I): 4.5 / Num. measured all: 55699
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.2 %

Resolution (Å)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
3.41-3.470.824237480.3610.67690.1
9.26-86.3517.327748630.0430.0898.2

-
Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DUK

6duk


Resolution: 3.42→86.32 Å / SU ML: 0.45 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2441 804 4.89 %
Rwork0.2147 15637 -
obs0.2162 16441 98.23 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 167.26 Å2 / Biso mean: 79.6886 Å2 / Biso min: 36.07 Å2
Refinement stepCycle: final / Resolution: 3.42→86.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9303 0 124 0 9427
Biso mean--73.35 --
Num. residues----1151
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A4208X-RAY DIFFRACTION13.798TORSIONAL
12B4208X-RAY DIFFRACTION13.798TORSIONAL
13C4208X-RAY DIFFRACTION13.798TORSIONAL
14D4208X-RAY DIFFRACTION13.798TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.42-3.630.31941250.27962556268197
3.63-3.910.2941250.25932605273099
3.91-4.30.24731540.19612598275299
4.3-4.930.22191270.18492580270797
4.93-6.210.25221350.21012643277899
6.21-86.320.20691380.20722655279398
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.460.2339-0.97021.6402-0.24253.68940.05640.01-0.2347-0.0503-0.02520.18170.135-0.1120.00740.35820.0162-0.05230.46380.07080.4842-1.496917.159741.2872
21.4340.46350.53582.3014-0.6425.63670.1687-0.17980.25670.0996-0.04520.0154-0.2171-0.227-0.10490.3373-0.03690.06050.48240.01690.5137-2.445726.540980.4959
32.8793-0.15992.31442.5355-1.47556.6146-0.0111-0.2595-0.02410.35550.18330.2103-0.6743-0.2901-0.13470.4994-0.04830.10940.51880.0620.5232-37.161725.720880.6405
42.42070.2177-1.75242.6960.52919.43530.04730.0178-0.0230.03840.21430.0510.33090.1171-0.27110.3314-0.0219-0.05760.573-0.00250.5514-38.12814.914341.289
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'A' and resid 701 through 1007)A701 - 1007
2X-RAY DIFFRACTION2(chain 'B' and resid 701 through 1101)B701 - 1101
3X-RAY DIFFRACTION3(chain 'C' and resid 702 through 1007)C702 - 1007
4X-RAY DIFFRACTION4(chain 'D' and resid 701 through 1007)D701 - 1007

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more