[English] 日本語
Yorodumi
- PDB-9gzh: PDGFRA-T674I in complex with covalent ponatinib derivative 19 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 9gzh
TitlePDGFRA-T674I in complex with covalent ponatinib derivative 19
ComponentsPlatelet-derived growth factor receptor alpha
KeywordsTRANSFERASE / platelet-derived growth factor receptor alpha / PDGFRA / GIST / gastrointestinal stromal tumor / ponatinib / gatekeeper mutation / covalent drugs / drug resistance / resistance mutation / secondary mutation
Function / homology
Function and homology information


Imatinib-resistant PDGFR mutants / Sunitinib-resistant PDGFR mutants / Regorafenib-resistant PDGFR mutants / Sorafenib-resistant PDGFR mutants / PDGFR mutants bind TKIs / platelet-derived growth factor receptor-alpha signaling pathway / platelet-derived growth factor receptor-ligand complex / metanephric glomerular capillary formation / regulation of mesenchymal stem cell differentiation / luteinization ...Imatinib-resistant PDGFR mutants / Sunitinib-resistant PDGFR mutants / Regorafenib-resistant PDGFR mutants / Sorafenib-resistant PDGFR mutants / PDGFR mutants bind TKIs / platelet-derived growth factor receptor-alpha signaling pathway / platelet-derived growth factor receptor-ligand complex / metanephric glomerular capillary formation / regulation of mesenchymal stem cell differentiation / luteinization / positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway / platelet-derived growth factor binding / vascular endothelial growth factor binding / embryonic skeletal system morphogenesis / retina vasculature development in camera-type eye / embryonic digestive tract morphogenesis / Leydig cell differentiation / cardiac myofibril assembly / Signaling by PDGF / cell activation / male genitalia development / positive regulation of chemotaxis / phospholipase C activator activity / embryonic cranial skeleton morphogenesis / platelet-derived growth factor receptor binding / signal transduction involved in regulation of gene expression / face morphogenesis / estrogen metabolic process / adrenal gland development / odontogenesis of dentin-containing tooth / roof of mouth development / microvillus / platelet-derived growth factor receptor signaling pathway / white fat cell differentiation / negative regulation of platelet activation / hematopoietic progenitor cell differentiation / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / transmembrane receptor protein tyrosine kinase activity / extracellular matrix organization / Downstream signal transduction / positive regulation of calcium-mediated signaling / cell surface receptor protein tyrosine kinase signaling pathway / cell chemotaxis / cellular response to reactive oxygen species / regulation of actin cytoskeleton organization / cellular response to amino acid stimulus / lung development / wound healing / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / platelet aggregation / positive regulation of fibroblast proliferation / Constitutive Signaling by Aberrant PI3K in Cancer / cell junction / cell migration / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein autophosphorylation / in utero embryonic development / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / nuclear body / cilium / positive regulation of cell migration / external side of plasma membrane / positive regulation of cell population proliferation / endoplasmic reticulum membrane / protein-containing complex binding / Golgi apparatus / protein homodimerization activity / protein-containing complex / nucleoplasm / ATP binding / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Platelet-derived growth factor receptor alpha / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain ...Platelet-derived growth factor receptor alpha / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Platelet-derived growth factor receptor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsTeuber, A. / Rauh, D. / Mueller, M.P.
Funding support Germany, European Union, 5items
OrganizationGrant numberCountry
German Research Foundation (DFG)RA 1055/3-2 Germany
European Regional Development FundEFRE-800400European Union
German Federal Ministry for Education and Research01ZX2201B Germany
Other governmentNW21-062C Germany
Other privateEx-2021-0033
CitationJournal: J.Med.Chem. / Year: 2025
Title: Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST.
Authors: Schulz, T. / Gontla, R. / Teuber, A. / Beerbaum, M. / Fletcher, B.S. / Muhlenberg, T. / Kaitsiotou, H. / Hardick, J. / Jeyakumar, K. / Keul, M. / Muller, M.P. / Sievers, S. / Bauer, S. / Rauh, D.
History
DepositionOct 4, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Platelet-derived growth factor receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,9292
Polymers40,4381
Non-polymers4911
Water1,08160
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13190 Å2
Unit cell
Length a, b, c (Å)135.920, 135.920, 34.690
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number168
Space group name H-MP6
Space group name HallP6
Symmetry operation#1: x,y,z
#2: x-y,x,z
#3: y,-x+y,z
#4: -y,x-y,z
#5: -x+y,-x,z
#6: -x,-y,z

-
Components

#1: Protein Platelet-derived growth factor receptor alpha / PDGF-R-alpha / PDGFR-alpha / Alpha platelet-derived growth factor receptor / Alpha-type platelet- ...PDGF-R-alpha / PDGFR-alpha / Alpha platelet-derived growth factor receptor / Alpha-type platelet-derived growth factor receptor / CD140 antigen-like family member A / CD140a antigen / Platelet-derived growth factor alpha receptor / Platelet-derived growth factor receptor 2 / PDGFR-2


Mass: 40437.594 Da / Num. of mol.: 1 / Mutation: T674I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDGFRA, PDGFR2, RHEPDGFRA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P16234, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1IRC / 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-~{N}-[4-(propanoylamino)-3-(trifluoromethyl)phenyl]benzamide


Mass: 491.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H20F3N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.29 Å3/Da / Density % sol: 46.23 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / Details: 5 mg/mL, 18% PEG3350, 100 mM KCl

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.999 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 23, 2021
RadiationMonochromator: SI (III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 2.2→33.98 Å / Num. obs: 19061 / % possible obs: 100 % / Redundancy: 20 % / Biso Wilson estimate: 56.06 Å2 / CC1/2: 0.99 / Net I/σ(I): 19.17
Reflection shellResolution: 2.2→2.32 Å / Mean I/σ(I) obs: 2.89 / Num. unique obs: 2353 / CC1/2: 0.85

-
Processing

Software
NameVersionClassification
XDS1.14_3260data reduction
PHENIX1.14_3260refinement
XSCALEdata scaling
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→33.98 Å / SU ML: 0.2605 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 24.7002 / Stereochemistry target values: CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2147 953 5 %
Rwork0.1818 18108 -
obs0.1834 19061 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 67.14 Å2
Refinement stepCycle: LAST / Resolution: 2.2→33.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2181 0 36 60 2277
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00292284
X-RAY DIFFRACTIONf_angle_d0.62993101
X-RAY DIFFRACTIONf_chiral_restr0.0441339
X-RAY DIFFRACTIONf_plane_restr0.0031386
X-RAY DIFFRACTIONf_dihedral_angle_d10.53991329
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.320.29331350.25122566X-RAY DIFFRACTION100
2.32-2.460.25471340.23272549X-RAY DIFFRACTION100
2.46-2.650.29251350.24192545X-RAY DIFFRACTION100
2.65-2.920.23981350.232565X-RAY DIFFRACTION100
2.92-3.340.2691360.21212586X-RAY DIFFRACTION99.96
3.34-4.210.18641360.16592598X-RAY DIFFRACTION100
4.21-33.980.1871420.15262699X-RAY DIFFRACTION100
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)
15.55676148197-3.507849656192.360451716328.78183394654-0.1060570906345.930602730720.1648463818840.3017270725470.003124596670930.144596101626-0.00244553311635-0.616805029817-0.09614750745420.598526205574-0.0592228513960.550185689512-0.09059820886120.007009678102290.393428346662-0.03625007649750.583464138069-50.31470061046.976871059558.9187599804
25.347362778654.41131861058-0.5490320291533.954026157740.82457232775.567238209960.04435069975641.43528092586-0.0500236870694-0.8585460358420.484520250623-1.65061257922-0.3118768853810.86935315992-0.8920006737280.7976014644580.03507274624630.2025515895390.642417241486-0.0802002169190.961460368542-43.0582203845-2.374796461930.122061617167
34.569209887931.85610340693-2.184818667046.08260768094-1.363669141684.505684272950.240868776241-0.3075102806050.3154265638990.174056003474-0.118908893081-0.00670471962507-0.4077289254530.190877515699-0.1060363467040.4407687999870.0729334671112-0.02995117110730.4133616098630.01226043311560.438063445339-57.8332404081-4.2784246455911.2133889885
47.84490240307-0.407484986841-0.2429126503245.35889262833-0.3488131609532.03264822876-0.1409550964690.2093845942170.43661572037-0.119200323415-0.0202836646441-0.362754880731-0.08102636225790.02319422841490.1982022125620.4754772085520.015303404553-0.01090126907520.3200332977120.0446660623520.306608667684-55.026222376-12.90107459378.45946248577
53.50070305504-1.632583608350.128664587459.033268116384.102510238492.21843519835-0.2200564643750.209740231325-0.233494355855-0.2499307760310.234649580763-1.35653400236-0.1411788943020.816799254308-0.1041022979750.5315333713630.03699618668470.002251042382190.650126615290.030994934110.6491426915-41.0768128057-22.70088176349.5649737922
67.35046492825-1.66446879726-0.2777282355656.371914149620.2209435531081.25918974193-0.0282514406884-0.293309412799-0.7757360241640.2612688059130.142411996869-0.02033791625690.241560340332-0.00358137600448-0.07484745437360.5763191639730.0342497906878-0.03921901632140.3702056336940.05051071547890.453143062284-53.8070866809-28.02997325412.6044695651
72.560627418820.800961427823-2.895416193681.883150962550.4271161074884.35645138183-0.06960793183171.57004624012-0.332609349093-0.419088424457-0.206204935611.0582353211-0.240450710944-0.9325091511380.09443915591720.8157300984850.0359621358182-0.09598524677180.714339239432-0.08868894727480.72062534896-68.0306080057-22.91716828590.979022988026
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 584 through 634 )
2X-RAY DIFFRACTION2chain 'A' and (resid 635 through 651 )
3X-RAY DIFFRACTION3chain 'A' and (resid 652 through 791 )
4X-RAY DIFFRACTION4chain 'A' and (resid 792 through 849 )
5X-RAY DIFFRACTION5chain 'A' and (resid 850 through 873 )
6X-RAY DIFFRACTION6chain 'A' and (resid 874 through 942 )
7X-RAY DIFFRACTION7chain 'A' and (resid 943 through 957 )

+
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