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- PDB-4u0i: Crystal structure of KIT in complex with ponatinib -

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Basic information

Entry
Database: PDB / ID: 4u0i
TitleCrystal structure of KIT in complex with ponatinib
ComponentsMast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KIT / receptor tyrosine kinase / inhibitor / ponatinib / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants ...Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants / Signaling by extracellular domain mutants of KIT / stem cell factor receptor activity / hematopoietic stem cell migration / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / erythropoietin-mediated signaling pathway / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / positive regulation of dendritic cell cytokine production / Kit signaling pathway / regulation of bile acid metabolic process / positive regulation of small intestine smooth muscle contraction / mast cell differentiation / positive regulation of mast cell proliferation / mast cell chemotaxis / Fc receptor signaling pathway / glycosphingolipid metabolic process / mast cell proliferation / positive regulation of long-term neuronal synaptic plasticity / detection of mechanical stimulus involved in sensory perception of sound / positive regulation of pseudopodium assembly / positive regulation of mast cell cytokine production / immature B cell differentiation / melanocyte differentiation / germ cell migration / lymphoid progenitor cell differentiation / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / pigmentation / tongue development / megakaryocyte development / Regulation of KIT signaling / mast cell degranulation / stem cell population maintenance / positive regulation of Notch signaling pathway / cytokine binding / negative regulation of reproductive process / negative regulation of developmental process / spermatid development / growth factor binding / somatic stem cell population maintenance / hemopoiesis / T cell differentiation / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / positive regulation of phospholipase C activity / response to cadmium ion / ovarian follicle development / positive regulation of tyrosine phosphorylation of STAT protein / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SH2 domain binding / cell chemotaxis / B cell differentiation / erythrocyte differentiation / acrosomal vesicle / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / epithelial cell proliferation / stem cell differentiation / positive regulation of receptor signaling pathway via JAK-STAT / visual learning / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / receptor protein-tyrosine kinase / fibrillar center / cytokine-mediated signaling pathway / male gonad development / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of DNA-binding transcription factor activity / cell-cell junction / PIP3 activates AKT signaling / regulation of cell population proliferation / regulation of cell shape / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / actin cytoskeleton organization / RAF/MAP kinase cascade / spermatogenesis / protein tyrosine kinase activity / protease binding / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / intracellular signal transduction / positive regulation of cell migration / inflammatory response
Similarity search - Function
Mast/stem cell growth factor receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. ...Mast/stem cell growth factor receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-0LI / PHOSPHATE ION / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsZhou, T. / Zhu, X. / Dalgarno, D.C.
CitationJournal: Clin.Cancer Res. / Year: 2014
Title: Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients.
Authors: Garner, A.P. / Gozgit, J.M. / Anjum, R. / Vodala, S. / Schrock, A. / Zhou, T. / Serrano, C. / Eilers, G. / Zhu, M. / Ketzer, J. / Wardwell, S. / Ning, Y. / Song, Y. / Kohlmann, A. / Wang, F. ...Authors: Garner, A.P. / Gozgit, J.M. / Anjum, R. / Vodala, S. / Schrock, A. / Zhou, T. / Serrano, C. / Eilers, G. / Zhu, M. / Ketzer, J. / Wardwell, S. / Ning, Y. / Song, Y. / Kohlmann, A. / Wang, F. / Clackson, T. / Heinrich, M.C. / Fletcher, J.A. / Bauer, S. / Rivera, V.M.
History
DepositionJul 11, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 8, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 26, 2014Group: Database references
Revision 1.2Nov 22, 2017Group: Derived calculations / Other ...Derived calculations / Other / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_database_status ...entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / refine_hist
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3394
Polymers35,6161
Non-polymers7233
Water2,468137
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area330 Å2
ΔGint-10 kcal/mol
Surface area14240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.032, 70.032, 129.212
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit / SCFR / Piebald trait protein / PBT / Proto-oncogene c-Kit / Tyrosine-protein kinase Kit / p145 c- ...SCFR / Piebald trait protein / PBT / Proto-oncogene c-Kit / Tyrosine-protein kinase Kit / p145 c-kit / v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog


Mass: 35616.195 Da / Num. of mol.: 1
Fragment: UNP residues 563-693 and 754-935 linked via linker (THR SER)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-0LI / 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide / Ponatinib / Ponatinib


Mass: 532.559 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H27F3N6O / Comment: medication*YM
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 137 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

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

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Sample preparation

CrystalDensity Matthews: 2.57 Å3/Da / Density % sol: 52.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1M Tris pH 8.5, 0.9-1.2M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Aug 27, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 25483 / % possible obs: 100 % / Redundancy: 8.2 % / Rmerge(I) obs: 0.102 / Χ2: 1.062 / Net I/av σ(I): 21.708 / Net I/σ(I): 7.5 / Num. measured all: 207978
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2-2.077.20.69424960.97599.9
2.07-2.1580.55624850.985100
2.15-2.258.30.44325281.042100
2.25-2.378.30.34325001.02100
2.37-2.528.30.27125071.081100
2.52-2.718.40.19325411.124100
2.71-2.998.40.14325421.124100
2.99-3.428.40.08625701.148100
3.42-4.318.40.04925841.094100
4.31-5080.03627301.00199.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
StructureStudiodata collection
HKL-2000data scaling
EPMRphasing
CNX3.14refinement
Quantamodel building
CNSrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→50 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.2388 1164 4.6 %
Rwork0.204 22943 -
obs-24107 94.7 %
Displacement parametersBiso max: 59.96 Å2 / Biso mean: 27.9818 Å2 / Biso min: 14.33 Å2
Baniso -1Baniso -2Baniso -3
1--0.096 Å20.078 Å20 Å2
2---0.096 Å20 Å2
3---0.193 Å2
Refinement stepCycle: final / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2356 0 186 0 2542
Biso mean--31.35 --
Num. residues----297
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.1351.5
X-RAY DIFFRACTIONc_scbond_it1.8542
X-RAY DIFFRACTIONc_mcangle_it1.7532
X-RAY DIFFRACTIONc_scangle_it2.6052.5
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2dna-rna_rep.param
X-RAY DIFFRACTION3water_rep.param
X-RAY DIFFRACTION4ion.param
X-RAY DIFFRACTION5AP24534_Kit.param

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