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- PDB-6xv9: Crystal structure of the kinase domain of human c-KIT in complex ... -

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Basic information

Entry
Database: PDB / ID: 6xv9
TitleCrystal structure of the kinase domain of human c-KIT in complex with a type-II inhibitor
ComponentsMast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
KeywordsSIGNALING PROTEIN / type II kinase inhibitor / structure-based drug design
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 / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / Kit signaling pathway / positive regulation of dendritic cell cytokine production / regulation of bile acid metabolic process / positive regulation of small intestine smooth muscle contraction / immature B cell differentiation / 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 / lymphoid progenitor cell differentiation / melanocyte differentiation / germ cell migration / myeloid progenitor cell differentiation / digestive tract development / erythropoietin-mediated signaling pathway / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / tongue development / pigmentation / megakaryocyte development / Regulation of KIT signaling / stem cell population maintenance / mast cell degranulation / positive regulation of Notch signaling pathway / negative regulation of reproductive process / negative regulation of developmental process / cytokine binding / growth factor binding / somatic stem cell population maintenance / hemopoiesis / ectopic germ cell programmed cell death / spermatid development / T cell differentiation / hematopoietic progenitor cell differentiation / Transcriptional and post-translational regulation of MITF-M expression and 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 / B cell differentiation / acrosomal vesicle / cell chemotaxis / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / epithelial cell proliferation / stem cell differentiation / positive regulation of DNA-binding transcription factor activity / positive regulation of receptor signaling pathway via JAK-STAT / visual learning / Signaling by SCF-KIT / receptor protein-tyrosine kinase / cytokine-mediated signaling pathway / fibrillar center / cytoplasmic side of plasma membrane / Constitutive Signaling by Aberrant PI3K in Cancer / male gonad development / cell-cell junction / PIP3 activates AKT signaling / regulation of cell shape / regulation of cell population proliferation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / actin cytoskeleton organization / RAF/MAP kinase cascade / protein tyrosine kinase activity / spermatogenesis / protease binding / protein autophosphorylation / positive regulation of MAPK cascade / 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 ...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 / 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
Similarity search - Domain/homology
Chem-O35 / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.38 Å
AuthorsOgg, D.J. / Howard, T. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Bernardes, G.J.L. ...Ogg, D.J. / Howard, T. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Bernardes, G.J.L. / Ward, R.A. / Kettle, J.G. / Waring, M.J.
CitationJournal: J.Am.Chem.Soc. / Year: 2020
Title: Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.
Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / ...Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / Waring, M.J. / Kettle, J.G.
History
DepositionJan 21, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2May 1, 2024Group: 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

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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
B: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,6384
Polymers74,6652
Non-polymers9732
Water00
1
A: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8192
Polymers37,3331
Non-polymers4871
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8192
Polymers37,3331
Non-polymers4871
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.632, 90.614, 87.042
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 37332.578 Da / Num. of mol.: 2
Fragment: protein kinase domain (551-934 del[688-755]),protein kinase domain (551-934 del[688-755]),protein kinase domain (551-934 del[688-755]),protein kinase domain (551-934 del[688-755])
Mutation: I563S,V569S,Y609Q,L631S,M651E,I662H,D768H,R804N,V825D,C844S,L890S,H894Y,L912D,L923D
Source method: isolated from a genetically manipulated source
Details: co-expression with PTPN1 (P18031-1) / Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 Star (DE3)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-O35 / ~{N}-[3-[(dimethylamino)methyl]-5-methyl-phenyl]-2-[3-methoxy-5-(7-methoxyquinolin-4-yl)oxy-pyridin-2-yl]ethanamide


Mass: 486.562 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H30N4O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 2.37 Å3/Da / Density % sol: 48.04 % / Mosaicity: 0.26 °
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 10 % PEG4000, 20 % glycerol, 10 % MORPHEUS halogens, 0.1 M Imidazole-MES buffer pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 8, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 3.38→90.61 Å / Num. obs: 10347 / % possible obs: 99.6 % / Redundancy: 4.7 % / Biso Wilson estimate: 71.33 Å2 / CC1/2: 0.984 / Rmerge(I) obs: 0.219 / Rpim(I) all: 0.111 / Rrim(I) all: 0.246 / Net I/σ(I): 6.3 / Num. measured all: 49007
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.38-3.574.80.664713714760.8060.3350.7462.199.8
10.7-90.6140.1115573900.990.0570.12514.999.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation7.23 Å63.72 Å
Translation7.23 Å63.72 Å

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.5.12data scaling
PHASER2.5.7phasing
BUSTERrefinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 3.38→63.72 Å / Cor.coef. Fo:Fc: 0.9051 / Cor.coef. Fo:Fc free: 0.8609 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.564
RfactorNum. reflection% reflectionSelection details
Rfree0.2466 507 4.92 %RANDOM
Rwork0.1946 ---
obs0.197 10307 99.34 %-
Displacement parametersBiso max: 238.25 Å2 / Biso mean: 84.61 Å2 / Biso min: 34.56 Å2
Baniso -1Baniso -2Baniso -3
1--8.2175 Å20 Å20 Å2
2--18.0282 Å20 Å2
3----9.8107 Å2
Refine analyzeLuzzati coordinate error obs: 0.418 Å
Refinement stepCycle: final / Resolution: 3.38→63.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4771 0 72 0 4843
Biso mean--59.9 --
Num. residues----598
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1710SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes110HARMONIC2
X-RAY DIFFRACTIONt_gen_planes776HARMONIC5
X-RAY DIFFRACTIONt_it4976HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion617SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5580SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4976HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6734HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion2.74
X-RAY DIFFRACTIONt_other_torsion20.23
LS refinement shellResolution: 3.38→3.78 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2773 174 6.08 %
Rwork0.2075 2689 -
all0.2119 2863 -
obs--99.1 %
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)
11.572-0.64680.27295.6809-0.88811.6376-0.033-0.0629-0.11970.1544-0.0164-0.0202-0.0541-0.04370.0494-0.1364-0.0307-0.0468-0.195-0.0047-0.1008186.34916.543370.5804
24.5632-0.5942-0.81524.16980.14931.6410.0776-0.04760.04930.3158-0.0839-0.8358-0.02170.3740.0063-0.1123-0.0125-0.1128-0.12460.1320.0903180.32220.5427107.07
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A566 - 931
2X-RAY DIFFRACTION2{ B|* }B572 - 931

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