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- PDB-1t46: STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF... -

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Basic information

Entry
Database: PDB / ID: 1t46
TitleSTRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF C-KIT TYROSINE KINASE
ComponentsHomo sapiens v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
KeywordsTRANSFERASE ACTIVATOR / KINASE / INHIBITOR / STI-571 / Gleevec
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 / immature B cell differentiation / melanocyte differentiation / positive regulation of mast cell cytokine production / lymphoid progenitor cell differentiation / germ cell migration / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / tongue development / megakaryocyte development / Regulation of KIT signaling / pigmentation / stem cell population maintenance / mast cell degranulation / positive regulation of Notch signaling pathway / cytokine binding / negative regulation of reproductive process / negative regulation of developmental process / growth factor binding / somatic stem cell population maintenance / hemopoiesis / T cell differentiation / spermatid development / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / : / 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 / B cell differentiation / erythrocyte differentiation / cell chemotaxis / 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 / receptor protein-tyrosine kinase / cytoplasmic side of plasma membrane / fibrillar center / cytokine-mediated signaling pathway / positive regulation of DNA-binding transcription factor activity / Constitutive Signaling by Aberrant PI3K in Cancer / male gonad development / 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
PHOSPHATE ION / Chem-STI / : / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsMol, C.D. / Dougan, D.R. / Schneider, T.R. / Skene, R.J. / Kraus, M.L. / Scheibe, D.N. / Snell, G.P. / Zou, H. / Sang, B.C. / Wilson, K.P.
CitationJournal: J.Biol.Chem. / Year: 2004
Title: Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase.
Authors: Mol, C.D. / Dougan, D.R. / Schneider, T.R. / Skene, R.J. / Kraus, M.L. / Scheibe, D.N. / Snell, G.P. / Zou, H. / Sang, B.C. / Wilson, K.P.
History
DepositionApr 28, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 15, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 23, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.4Feb 14, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 999SEQUENCE THIS IS A RECEPTOR PROTEIN TYROSINE KINASE WITH A "SPLIT" KINASE DOMAIN. THUS THE TWO ...SEQUENCE THIS IS A RECEPTOR PROTEIN TYROSINE KINASE WITH A "SPLIT" KINASE DOMAIN. THUS THE TWO CONSERVED KINASE DOMAINS ARE INTERRUPTED BY A LARGE NON-CONSERVED INSERTION CALLED THE KINASE INSERTION DOMAIN (KID). IN THE CONSTRUCT THE KID RESIDUES 694-753 WERE DELETED AND REPLACED WITH TWO VECTOR RESIDUES (THR-SER).

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Structure visualization

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Assembly

Deposited unit
A: Homo sapiens v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0724
Polymers35,3891
Non-polymers6843
Water4,828268
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)70.089, 70.089, 127.880
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Homo sapiens v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog


Mass: 35388.934 Da / Num. of mol.: 1 / Fragment: tyrosine kinase
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: kit / Plasmid: PSXB1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P10721, GenBank: 4557695, EC: 2.7.1.112
#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-STI / 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE / STI-571 / IMATINIB


Mass: 493.603 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H31N7O / Comment: medication, inhibitor*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / 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: 2.4 Å3/Da / Density % sol: 50 %
Crystal growTemperature: 275 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: PHOSPHATE, pH 8.50, VAPOR DIFFUSION, SITTING DROP, temperature 275K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 16, 2003 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→30 Å / Num. all: 48006 / Num. obs: 48006 / % possible obs: 98.4 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 4.6 % / Rmerge(I) obs: 0.028 / Net I/σ(I): 19.3
Reflection shellResolution: 1.6→1.66 Å / Rmerge(I) obs: 0.367 / Mean I/σ(I) obs: 2.6 / % possible all: 90

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
AMoREphasing
REFMAC5.1.19refinement
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→20 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.955 / SU B: 1.717 / SU ML: 0.059 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.086 / ESU R Free: 0.085 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21291 2406 5 %RANDOM
Rwork0.1884 ---
all0.18963 45483 --
obs0.18963 45483 98.39 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 23.459 Å2
Baniso -1Baniso -2Baniso -3
1-1.18 Å20.59 Å20 Å2
2--1.18 Å20 Å2
3----1.78 Å2
Refinement stepCycle: LAST / Resolution: 1.6→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2381 0 47 268 2696
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222487
X-RAY DIFFRACTIONr_angle_refined_deg1.0851.983368
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.055295
X-RAY DIFFRACTIONr_chiral_restr0.0750.2366
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021853
X-RAY DIFFRACTIONr_nbd_refined0.1930.21328
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1180.2252
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1650.268
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1530.221
X-RAY DIFFRACTIONr_mcbond_it1.48121485
X-RAY DIFFRACTIONr_mcangle_it2.47132402
X-RAY DIFFRACTIONr_scbond_it1.86621002
X-RAY DIFFRACTIONr_scangle_it2.8253966
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.276 159
Rwork0.245 2980

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