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- PDB-1t45: STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF... -

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Basic information

Entry
Database: PDB / ID: 1t45
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 / AUTOINHIBITION
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
: / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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: Advisory / Version format compliance
Revision 1.3Aug 23, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.4Aug 23, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
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

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)37,6701
Polymers37,6701
Non-polymers00
Water2,990166
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.414, 77.230, 94.574
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 37669.559 Da / Num. of mol.: 1 / Fragment: KIT 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: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 166 / 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: 2.2 Å3/Da / Density % sol: 42 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 7
Details: PEG, pH 7.00, VAPOR DIFFUSION, SITTING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jul 10, 2003 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
211
ReflectionResolution: 1.9→30 Å / Num. all: 26260 / Num. obs: 26260 / % possible obs: 99.3 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 4 / Redundancy: 4.1 % / Biso Wilson estimate: 20 Å2 / Rmerge(I) obs: 0.058 / Net I/σ(I): 12.6
Reflection shellResolution: 1.9→1.97 Å / Rmerge(I) obs: 0.345 / Mean I/σ(I) obs: 3.1 / % possible all: 96.5

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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
Starting model: 1PKG

1pkg


Resolution: 1.9→20 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.936 / SU B: 3.379 / SU ML: 0.1 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.17 / ESU R Free: 0.145 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22154 1325 5.1 %RANDOM
Rwork0.19299 ---
all0.19446 24835 --
obs0.19446 24835 99.37 %-
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: 16.896 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20 Å20 Å2
2--1.7 Å20 Å2
3----1.75 Å2
Refinement stepCycle: LAST / Resolution: 1.9→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2642 0 0 166 2808
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222719
X-RAY DIFFRACTIONr_bond_other_d0.0020.022470
X-RAY DIFFRACTIONr_angle_refined_deg1.1121.9583679
X-RAY DIFFRACTIONr_angle_other_deg0.75935768
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3035329
X-RAY DIFFRACTIONr_chiral_restr0.0650.2404
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022959
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02548
X-RAY DIFFRACTIONr_nbd_refined0.2030.2587
X-RAY DIFFRACTIONr_nbd_other0.2280.23014
X-RAY DIFFRACTIONr_nbtor_other0.0830.21592
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2155
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1120.217
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2450.277
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1170.214
X-RAY DIFFRACTIONr_mcbond_it0.5371.51653
X-RAY DIFFRACTIONr_mcangle_it0.8841.52675
X-RAY DIFFRACTIONr_scbond_it0.4961.51066
X-RAY DIFFRACTIONr_scangle_it0.7291.51002
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.28 85
Rwork0.228 1713
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)
11.1534-0.11890.00941.7019-0.11872.22160.0289-0.0128-0.0407-0.0333-0.04240.0159-0.1834-0.05130.01350.0187-0.0064-0.00210.02340.00450.07619.64414.5479.965
21.55820.1885-0.19072.3859-0.32842.0227-0.0148-0.0683-0.14490.08040.02140.1093-0.0543-0.0149-0.00670.0109-0.0037-0.00240.02050.00860.06994.6034.05330.616
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA547 - 6751 - 129
2X-RAY DIFFRACTION2AA676 - 935130 - 331

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