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- PDB-4hvs: Crystal structure of KIT kinase domain with a small molecule inhi... -

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Basic information

Entry
Database: PDB / ID: 4hvs
TitleCrystal structure of KIT kinase domain with a small molecule inhibitor, PLX647
ComponentsMast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / transferase / tyrosine-protein kinase / ATP-binding / kinase-kinase inhibitor complex / 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 / hematopoietic stem cell migration / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / Kit signaling pathway / positive regulation of small intestine smooth muscle contraction / regulation of bile acid metabolic process / positive regulation of dendritic cell cytokine production / positive regulation of mast cell proliferation / mast cell differentiation / 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 / positive regulation of mast cell cytokine production / lymphoid progenitor cell differentiation / melanocyte differentiation / germ cell migration / erythropoietin-mediated signaling pathway / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / lamellipodium assembly / embryonic hemopoiesis / tongue development / positive regulation of tyrosine phosphorylation of STAT protein / Regulation of KIT signaling / megakaryocyte development / mast cell degranulation / pigmentation / stem cell population maintenance / positive regulation of Notch signaling pathway / growth factor binding / cytokine binding / spermatid development / negative regulation of reproductive process / negative regulation of developmental process / hemopoiesis / somatic stem cell population maintenance / T cell differentiation / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / response to cadmium ion / ovarian follicle development / transmembrane receptor protein tyrosine kinase activity / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / Transcriptional and post-translational regulation of MITF-M expression and activity / B cell differentiation / SH2 domain binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / acrosomal vesicle / erythrocyte differentiation / positive regulation of DNA-binding transcription factor activity / epithelial cell proliferation / cell chemotaxis / positive regulation of receptor signaling pathway via JAK-STAT / stem cell differentiation / placental growth factor receptor activity / Signaling by SCF-KIT / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / cytokine-mediated signaling pathway / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / visual learning / cytoplasmic side of plasma membrane / fibrillar center / male gonad development / Constitutive Signaling by Aberrant PI3K in Cancer / cell-cell junction / cell migration
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 ...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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase); domain 1 / 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-647 / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsZhang, Y. / Zhang, C.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2013
Title: Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.
Authors: Zhang, C. / Ibrahim, P.N. / Zhang, J. / Burton, E.A. / Habets, G. / Zhang, Y. / Powell, B. / West, B.L. / Matusow, B. / Tsang, G. / Shellooe, R. / Carias, H. / Nguyen, H. / Marimuthu, A. / ...Authors: Zhang, C. / Ibrahim, P.N. / Zhang, J. / Burton, E.A. / Habets, G. / Zhang, Y. / Powell, B. / West, B.L. / Matusow, B. / Tsang, G. / Shellooe, R. / Carias, H. / Nguyen, H. / Marimuthu, A. / Zhang, K.Y. / Oh, A. / Bremer, R. / Hurt, C.R. / Artis, D.R. / Wu, G. / Nespi, M. / Spevak, W. / Lin, P. / Nolop, K. / Hirth, P. / Tesch, G.H. / Bollag, G.
History
DepositionNov 6, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 17, 2013Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4242
Polymers38,0421
Non-polymers3821
Water1,946108
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Mast/stem cell growth factor receptor Kit
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)76,8494
Polymers76,0842
Non-polymers7652
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area1080 Å2
ΔGint-12 kcal/mol
Surface area28850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.735, 81.863, 50.055
Angle α, β, γ (deg.)90.00, 107.81, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1167-

HOH

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Components

#1: Protein 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: 38042.102 Da / Num. of mol.: 1 / Fragment: KIT kinase domain with KID deleted
Mutation: I563S, V569S, Y609Q, L631S, M651E, I662H, I690H, C691S, K693D, I756S, L762N, V825D, C844S, L890S, L912D, L923D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Production host: Escherichia coli (E. coli)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-647 / 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-[4-(trifluoromethyl)benzyl]pyridin-2-amine


Mass: 382.382 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17F3N4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / 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: 2.84 Å3/Da / Density % sol: 56.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 1.6M ammonium sulfate, 2.0M sodium Chloride and 0.1M Bis-Tris, pH 6.0, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.1159 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 10, 2012
RadiationMonochromator: Double flat crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1159 Å / Relative weight: 1
ReflectionResolution: 1.85→64.66 Å / Num. all: 36347 / Num. obs: 35908 / % possible obs: 98.8 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3
Reflection shellResolution: 1.85→1.95 Å / % possible all: 98.8

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Processing

Software
NameVersionClassification
MOLREPphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1T45

1t45


Resolution: 1.9→52.7 Å / SU ML: 0.25 / σ(F): 0 / Phase error: 22.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.227 1632 4.92 %RANDOM
Rwork0.199 ---
all0.2003 33573 --
obs0.2003 33194 98.87 %-
Solvent computationShrinkage radii: 0.86 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 32.117 Å2 / ksol: 0.4 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-2.2674 Å20 Å20.7502 Å2
2---2.8198 Å20 Å2
3---0.5524 Å2
Refinement stepCycle: LAST / Resolution: 1.9→52.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2592 0 28 108 2728
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0142689
X-RAY DIFFRACTIONf_angle_d1.4113640
X-RAY DIFFRACTIONf_dihedral_angle_d14.942984
X-RAY DIFFRACTIONf_chiral_restr0.098382
X-RAY DIFFRACTIONf_plane_restr0.006467
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.95590.3391390.29262607X-RAY DIFFRACTION98
1.9559-2.01910.26061540.2482604X-RAY DIFFRACTION98
2.0191-2.09120.29841570.2232562X-RAY DIFFRACTION98
2.0912-2.1750.21781240.21342603X-RAY DIFFRACTION99
2.175-2.2740.25831320.20112639X-RAY DIFFRACTION98
2.274-2.39390.20991320.21212597X-RAY DIFFRACTION99
2.3939-2.54380.2291230.20752656X-RAY DIFFRACTION99
2.5438-2.74020.26491170.20982641X-RAY DIFFRACTION99
2.7402-3.0160.22591330.22352624X-RAY DIFFRACTION99
3.016-3.45230.22051600.20162645X-RAY DIFFRACTION100
3.4523-4.34930.19751340.1742660X-RAY DIFFRACTION99
4.3493-52.73430.21061270.17412724X-RAY DIFFRACTION100

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