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- PDB-6kla: Crystal structure of human c-KIT kinase domain in complex with co... -

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Basic information

Entry
Database: PDB / ID: 6kla
TitleCrystal structure of human c-KIT kinase domain in complex with compound 15a
ComponentsMast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE / tyrosine kinase inhibitor / kinase phosphorylation / ATP competitor / transmembrane receptor protein
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
Chem-DJX / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.109 Å
AuthorsWu, T.S. / Peng, Y.H. / Hsueh, C.C. / Wu, S.Y.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia.
Authors: Lin, W.H. / Wu, S.Y. / Yeh, T.K. / Chen, C.T. / Song, J.S. / Shiao, H.Y. / Kuo, C.C. / Hsu, T. / Lu, C.T. / Wang, P.C. / Wu, T.S. / Peng, Y.H. / Lin, H.Y. / Chen, C.P. / Weng, Y.L. / Kung, F. ...Authors: Lin, W.H. / Wu, S.Y. / Yeh, T.K. / Chen, C.T. / Song, J.S. / Shiao, H.Y. / Kuo, C.C. / Hsu, T. / Lu, C.T. / Wang, P.C. / Wu, T.S. / Peng, Y.H. / Lin, H.Y. / Chen, C.P. / Weng, Y.L. / Kung, F.C. / Wu, M.H. / Su, Y.C. / Huang, K.W. / Chou, L.H. / Hsueh, C.C. / Yen, K.J. / Kuo, P.C. / Huang, C.L. / Chen, L.T. / Shih, C. / Tsai, H.J. / Jiaang, W.T.
History
DepositionJul 30, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 8, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Nov 22, 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

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0512
Polymers37,6701
Non-polymers3811
Water84747
1
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)76,1024
Polymers75,3392
Non-polymers7632
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area1850 Å2
ΔGint-4 kcal/mol
Surface area28200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.205, 63.205, 196.142
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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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: 37669.559 Da / Num. of mol.: 1
Fragment: kinase domain, residue 547-693 and 754-935 from UNP P10721, linked with TS
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Plasmid: pBacPAK8 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-DJX / N-[6-(4-ethylpiperazin-1-yl)-2-methyl-pyrimidin-4-yl]-5-pyridin-4-yl-1,3-thiazol-2-amine / 6-(4-ethylpiperazin-1-yl)-2-methyl-N-(5-(pyridin-4-yl)thiazol-2-yl)pyrimidin-4-amine


Mass: 381.498 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23N7S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 47 / Source method: isolated from a natural source / Formula: H2O
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: 2.6 Å3/Da / Density % sol: 52.69 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: PEG 4000, sodium citrate tribasic dihydrate, pH5.6, glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: TPS 05A / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Mar 4, 2017 / Details: LN2-Cooled Fixed-Exit Double
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.109→30 Å / Num. obs: 23502 / % possible obs: 98.3 % / Redundancy: 7.2 % / Biso Wilson estimate: 45.25 Å2 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.026 / Rrim(I) all: 0.071 / Χ2: 1.051 / Net I/σ(I): 12.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.11-2.194.90.62121230.8990.2780.6841.05992
2.19-2.276.10.50922850.9590.2140.5541.02798.1
2.27-2.387.20.40922940.9830.1610.441.07399
2.38-2.57.80.3423470.9860.1290.3641.03199.3
2.5-2.6680.2323430.9930.0860.2461.08999.3
2.66-2.8680.14823510.9960.0550.1581.04699.4
2.86-3.157.90.09423630.9960.0350.11.05899.5
3.15-3.617.60.06223830.9980.0240.0661.05899.5
3.61-4.547.30.04724440.9980.0180.051.02599.1
4.54-306.80.04325690.9980.0170.0471.03897.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXdev_2621refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1T46

1t46


Resolution: 2.109→29.482 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.78
RfactorNum. reflection% reflection
Rfree0.2239 1996 8.52 %
Rwork0.183 --
obs0.1866 23419 98.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 148.74 Å2 / Biso mean: 64.5664 Å2 / Biso min: 29.29 Å2
Refinement stepCycle: final / Resolution: 2.109→29.482 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2423 0 27 47 2497
Biso mean--49.86 56.03 -
Num. residues----309
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072560
X-RAY DIFFRACTIONf_angle_d0.833465
X-RAY DIFFRACTIONf_chiral_restr0.052374
X-RAY DIFFRACTIONf_plane_restr0.005438
X-RAY DIFFRACTIONf_dihedral_angle_d10.222119
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection Rwork% reflection obs (%)
2.1094-2.16220.36881251133990
2.1622-2.22060.2657138147497
2.2206-2.28590.2927140149398
2.2859-2.35970.2977139150298
2.3597-2.4440.2697140150899
2.444-2.54180.2642143153399
2.5418-2.65740.28142152199
2.6574-2.79740.2856142152499
2.7974-2.97250.2717142153499
2.9725-3.20180.26231461566100
3.2018-3.52350.2131451564100
3.5235-4.03230.21761470.17241571100
4.0323-5.0760.18961480.1394159599
5.076-29.4820.18291590.1639169998
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)
16.7458-2.1375-1.41173.0633.99115.85140.36451.0469-0.4644-0.01150.2297-0.52570.95170.3462-0.70870.73570.07-0.10720.8679-0.11440.67537.10660.843122.2893
27.73251.52360.43768.87770.54266.185-0.086-0.70240.06250.1594-0.07340.27110.0188-0.33970.17410.29090.00930.02620.39870.01310.192315.908211.821529.4448
39.0952-4.41183.41887.8753-3.04253.7584-0.0282-0.38570.07450.71120.42030.7173-0.2433-0.3534-0.4110.3419-0.06080.05550.3969-0.04480.279713.893611.657627.1093
44.14574.1674-5.56819.5754-6.20127.641-0.2498-0.2037-0.14630.31980.2388-0.64240.66120.3679-0.15160.42970.0181-0.10060.4601-0.08920.593227.90574.448528.5177
52.06860.3080.3962.81472.15276.57120.02330.1131-0.0521-0.06950.07560.2140.4559-0.5966-0.09430.3754-0.0856-0.01950.38710.03010.379614.84645.647415.7819
63.12071.22833.92565.78051.31965.975-0.32270.37320.1004-0.54520.27350.08380.09130.049-0.05620.3814-0.07180.06710.4137-0.01590.256718.76333.5240.9536
72.4162-1.20180.52823.16390.59533.6242-0.0138-0.2656-0.52350.40860.2464-0.00241.1050.1444-0.21220.7074-0.0008-0.0040.42850.02260.449822.2022-10.287511.1728
86.7392-1.29891.75795.45160.0835.53070.11050.45130.1896-0.51710.1146-0.55260.23850.4289-0.160.4815-0.0070.15130.5205-0.10970.408828.9063-3.7273-2.6573
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 554 through 579 )A554 - 579
2X-RAY DIFFRACTION2chain 'A' and (resid 580 through 600 )A580 - 600
3X-RAY DIFFRACTION3chain 'A' and (resid 601 through 630 )A601 - 630
4X-RAY DIFFRACTION4chain 'A' and (resid 631 through 647 )A631 - 647
5X-RAY DIFFRACTION5chain 'A' and (resid 648 through 758 )A648 - 758
6X-RAY DIFFRACTION6chain 'A' and (resid 759 through 786 )A759 - 786
7X-RAY DIFFRACTION7chain 'A' and (resid 787 through 896 )A787 - 896
8X-RAY DIFFRACTION8chain 'A' and (resid 897 through 931 )A897 - 931

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