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- PDB-3g0f: KIT kinase domain mutant D816H in complex with sunitinib -

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Basic information

Entry
Database: PDB / ID: 3g0f
TitleKIT kinase domain mutant D816H in complex with sunitinib
ComponentsMast/stem cell growth factor receptor
KeywordsTRANSFERASE / KIT Kinase domain / Sutent binding / drug resistance / ATP-binding / Disease mutation / Glycoprotein / Immunoglobulin domain / Kinase / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Proto-oncogene / Receptor / Transmembrane / Tyrosine-protein kinase
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-B49 / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsGajiwala, K.S. / Wu, J.C. / Lunney, E.A. / Demetri, G.D.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2009
Title: KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.
Authors: Gajiwala, K.S. / Wu, J.C. / Christensen, J. / Deshmukh, G.D. / Diehl, W. / DiNitto, J.P. / English, J.M. / Greig, M.J. / He, Y.A. / Jacques, S.L. / Lunney, E.A. / McTigue, M. / Molina, D. / ...Authors: Gajiwala, K.S. / Wu, J.C. / Christensen, J. / Deshmukh, G.D. / Diehl, W. / DiNitto, J.P. / English, J.M. / Greig, M.J. / He, Y.A. / Jacques, S.L. / Lunney, E.A. / McTigue, M. / Molina, D. / Quenzer, T. / Wells, P.A. / Yu, X. / Zhang, Y. / Zou, A. / Emmett, M.R. / Marshall, A.G. / Zhang, H.M. / Demetri, G.D.
History
DepositionJan 27, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 24, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 16, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_entity_nonpoly / struct_ref_seq_dif / struct_site
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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 29, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond / pdbx_database_related
Item: _pdbx_database_related.db_name
Revision 1.5Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)77,3735
Polymers76,4802
Non-polymers8933
Water27015
1
A: Mast/stem cell growth factor receptor
B: Mast/stem cell growth factor receptor
hetero molecules

A: Mast/stem cell growth factor receptor
B: Mast/stem cell growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)154,74710
Polymers152,9614
Non-polymers1,7866
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_575-x,-y+2,z1
Buried area11900 Å2
ΔGint-70 kcal/mol
Surface area48470 Å2
MethodPISA
2


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)79.462, 101.783, 105.505
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Mast/stem cell growth factor receptor / SCFR / Proto-oncogene tyrosine-protein kinase Kit / c-kit


Mass: 38240.238 Da / Num. of mol.: 2 / Fragment: Kinase domain - KID deleted / Mutation: 694-753 deleted, replaced with TS; D816H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIT / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-B49 / N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbo xamide / SUNITINIB / Sunitinib


Mass: 398.474 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H27FN4O2 / Comment: medication, anticancer, inhibitor*YM
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 15 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsRESIDUES 694-753 DELETED, REPLACED WITH TS

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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: 2.79 Å3/Da / Density % sol: 55.9 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1.5 M Ammonium sulfate, 286K, pH 7, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 1, 2007 / Details: Mirrors
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→20 Å / Num. all: 26965 / Num. obs: 26751 / % possible obs: 99.2 % / Redundancy: 4.6 % / Biso Wilson estimate: 30.6 Å2 / Rmerge(I) obs: 0.042 / Rsym value: 0.042
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.216 / Mean I/σ(I) obs: 7.6 / Num. unique all: 2683 / Rsym value: 0.216 / % possible all: 96.8

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Sunitinib bound wild-type kinase domain of KIT

Resolution: 2.6→20 Å / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.255 1307 -Random
Rwork0.204 ---
all0.212 26921 --
obs0.207 25905 95.9 %-
Refine analyze
FreeObs
Luzzati coordinate error0.38 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.36 Å0.3 Å
Refinement stepCycle: LAST / Resolution: 2.6→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4658 0 49 15 4722
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_dihedral_angle_d21
X-RAY DIFFRACTIONc_improper_angle_d0.66
LS refinement shellResolution: 2.6→2.76 Å / Rfactor Rfree error: 0.022
RfactorNum. reflection% reflection
Rfree0.316 205 -
Rwork0.27 --
obs-3747 89.3 %

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