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- PDB-6hh1: Structure of c-Kit with allosteric inhibitor 3G8 -

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Basic information

Entry
Database: PDB / ID: 6hh1
TitleStructure of c-Kit with allosteric inhibitor 3G8
ComponentsMast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE / c-Kit / kinase / allosteric / inhibitor
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
Chem-G4E / PHOSPHATE ION / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.25 Å
AuthorsWrasidlo, W.J. / Cheresh, D.A.
CitationJournal: To Be Published
Title: Structure of c-Kit with allosteric inhibitor 3G8
Authors: Wrasidlo, W.J. / Cheresh, D.A.
History
DepositionAug 24, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 18, 2019Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)34,6683
Polymers34,2161
Non-polymers4522
Water2,198122
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area170 Å2
ΔGint-5 kcal/mol
Surface area14850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.614, 65.614, 159.004
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: 34215.754 Da / Num. of mol.: 1
Mutation: V752T, T753S,V752T, T753S,V752T, T753S,V752T, T753S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-G4E / ~{N}-(2,3-dimethylphenyl)-5-(4-pyridin-4-yloxyphenyl)-4~{H}-1,2,4-triazol-3-amine


Mass: 357.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19N5O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.38 Å3/Da / Density % sol: 48.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 9.3 mg/mL protein in 250 mM NaCl, 25 mM Tris-HCl pH 7.4, 1 mM EDTA, 0.5 mM TCEP, 1.2 mM 3G8, 0.1% w/w V8 protease. 800 nL of protein was mixed with 800 nL of crystallization solution (0.1 M ...Details: 9.3 mg/mL protein in 250 mM NaCl, 25 mM Tris-HCl pH 7.4, 1 mM EDTA, 0.5 mM TCEP, 1.2 mM 3G8, 0.1% w/w V8 protease. 800 nL of protein was mixed with 800 nL of crystallization solution (0.1 M Tris-HCl pH 9.1, 1.5 M diammonium hydrogen phosphate) and incubated over 0.4 mL crystallization solution in 24 well VDX plates. Crystals were cryo-protected with 20% v/v ethylene glycol.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.15→20 Å / Num. obs: 21244 / % possible obs: 97.65 % / Observed criterion σ(I): -3 / Redundancy: 3.94 % / Rrim(I) all: 0.13 / Net I/σ(I): 5.42
Reflection shellResolution: 2.15→2.27 Å / Redundancy: 4.05 % / Mean I/σ(I) obs: 1.6 / Num. unique obs: 3110 / Rrim(I) all: 0.8 / % possible all: 99.81

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.25→25.32 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.926 / SU B: 19.61 / SU ML: 0.227 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.284 / ESU R Free: 0.244 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2734 940 5.1 %RANDOM
Rwork0.2045 ---
obs0.208 17585 94.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 118.4 Å2 / Biso mean: 62.078 Å2 / Biso min: 38.42 Å2
Baniso -1Baniso -2Baniso -3
1--0.94 Å2-0.47 Å2-0 Å2
2---0.94 Å20 Å2
3---3.05 Å2
Refinement stepCycle: final / Resolution: 2.25→25.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2400 0 32 122 2554
Biso mean--57.99 63.19 -
Num. residues----303
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0132518
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172369
X-RAY DIFFRACTIONr_angle_refined_deg1.8961.6563411
X-RAY DIFFRACTIONr_angle_other_deg1.3211.5855493
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8685309
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.87121.597119
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.93715440
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.0221515
X-RAY DIFFRACTIONr_chiral_restr0.0870.2321
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022773
X-RAY DIFFRACTIONr_gen_planes_other0.0070.02553
LS refinement shellResolution: 2.25→2.308 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.468 72 -
Rwork0.423 1244 -
all-1316 -
obs--93.67 %
Refinement TLS params.Method: refined / Origin x: 57.5998 Å / Origin y: 38.4738 Å / Origin z: 14.7802 Å
111213212223313233
T0.0671 Å20.0742 Å2-0.0349 Å2-0.4004 Å20.0881 Å2--0.0889 Å2
L2.4784 °20.1719 °20.146 °2-3.6107 °2-1.6358 °2--3.2065 °2
S0.1145 Å °-0.0421 Å °-0.1341 Å °-0.208 Å °0.0633 Å °0.4457 Å °-0.0059 Å °-0.1656 Å °-0.1778 Å °

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