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- PDB-6xvb: Crystal structure of the kinase domain of human c-KIT with a cycl... -

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Basic information

Entry
Database: PDB / ID: 6xvb
TitleCrystal structure of the kinase domain of human c-KIT with a cyclic imidate inhibitor covalently bound to Cys788
ComponentsMast/stem cell growth factor receptor Kit,Mast/stem cell growth factor receptor Kit
KeywordsSIGNALING PROTEIN / type II kinase inhibitor / structure-based drug design / covalent inhibitor / cysteine reactive warhead
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 / stem cell factor receptor activity / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / Kit signaling pathway / tongue development / : / positive regulation of small intestine smooth muscle contraction / positive regulation of dendritic cell cytokine production / mast cell chemotaxis / positive regulation of mast cell proliferation / mast cell differentiation / Fc receptor signaling pathway / glycosphingolipid metabolic process / mast cell proliferation / positive regulation of pseudopodium assembly / positive regulation of long-term neuronal synaptic plasticity / positive regulation of mast cell cytokine production / lymphoid progenitor cell differentiation / detection of mechanical stimulus involved in sensory perception of sound / melanocyte differentiation / immature B cell differentiation / germ cell migration / erythropoietin-mediated signaling pathway / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / positive regulation of tyrosine phosphorylation of STAT protein / Regulation of KIT signaling / megakaryocyte development / growth factor binding / mast cell degranulation / stem cell population maintenance / pigmentation / positive regulation of Notch signaling pathway / cytokine binding / negative regulation of reproductive process / negative regulation of developmental process / hemopoiesis / T cell differentiation / somatic stem cell population maintenance / spermatid development / ectopic germ cell programmed cell death / response to cadmium ion / hematopoietic progenitor cell differentiation / positive regulation of DNA-binding transcription factor activity / ovarian follicle development / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / Transcriptional and post-translational regulation of MITF-M expression and activity / acrosomal vesicle / SH2 domain binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / B cell differentiation / epithelial cell proliferation / erythrocyte differentiation / cell chemotaxis / positive regulation of receptor signaling pathway via JAK-STAT / stem cell differentiation / Signaling by SCF-KIT / receptor protein-tyrosine kinase / visual learning / cytoplasmic side of plasma membrane / male gonad development / fibrillar center / cytokine-mediated signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cell-cell junction / cell migration / PIP3 activates AKT signaling / regulation of cell shape / regulation of cell population proliferation / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / actin cytoskeleton organization / protease binding / protein tyrosine kinase activity / spermatogenesis / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / intracellular signal transduction / positive regulation of 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. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / 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-O2H / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsSchimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. ...Schimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.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
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)75,7464
Polymers74,6652
Non-polymers1,0812
Water1,69394
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)37,8732
Polymers37,3331
Non-polymers5411
Water181
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)37,8732
Polymers37,3331
Non-polymers5411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.710, 90.272, 91.178
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])
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 BL21(DE3) (bacteria) / Variant (production host): BL21 Star (DE3)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-O2H / ~{N}-(4,4-dimethyl-2-propyl-3,1-benzoxazin-6-yl)-2-[3-methoxy-5-(7-methoxyquinolin-4-yl)oxy-pyridin-2-yl]ethanamide


Mass: 540.610 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H32N4O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.42 Å3/Da / Density % sol: 49.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.2
Details: 9 % PEG8000, 18 % ethylene glycol, 10 % MORPHEUS halogens, 0.1 M Imidazole-MES buffer pH 6.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97623 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jun 28, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97623 Å / Relative weight: 1
ReflectionResolution: 2.15→63.211 Å / Num. obs: 35714 / % possible obs: 92.7 % / Redundancy: 6.7 % / Biso Wilson estimate: 55.24 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.096 / Net I/σ(I): 9.9
Reflection shellResolution: 2.15→2.251 Å / Redundancy: 1.4 % / Num. unique obs: 1783 / CC1/2: 0.509 / % possible all: 47.7

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 2.15→63.21 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.94 / SU R Cruickshank DPI: 0.23 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.228 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.182
RfactorNum. reflection% reflectionSelection details
Rfree0.223 1950 5.46 %RANDOM
Rwork0.192 ---
obs0.194 35714 89.3 %-
Displacement parametersBiso max: 160.5 Å2 / Biso mean: 66.71 Å2 / Biso min: 29.98 Å2
Baniso -1Baniso -2Baniso -3
1--3.3493 Å20 Å20 Å2
2--2.4448 Å20 Å2
3---0.9045 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: final / Resolution: 2.15→63.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4629 0 80 94 4803
Biso mean--60.77 56.98 -
Num. residues----585
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1659SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes800HARMONIC5
X-RAY DIFFRACTIONt_it4835HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion605SEMIHARMONIC5
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_contact5507SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4835HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6549HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.13
X-RAY DIFFRACTIONt_other_torsion17.65
LS refinement shellResolution: 2.15→2.21 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2683 48 6.71 %
Rwork0.216 667 -
all0.2194 715 -
obs--23.54 %
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)
11.5715-0.14750.65651.631-0.62923.748-0.0443-0.00260.05660.0229-0.0207-0.0192-0.0753-0.0140.0649-0.24120.06270.0272-0.1609-0.0105-0.1721-16.882537.951729.602
21.81211.048-0.17116.1808-0.05651.34420.01130.0272-0.35410.1149-0.0078-0.03620.25790.0971-0.0036-0.24620.0551-0.0072-0.17330.0046-0.139619.603444.644125.0523
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A569 - 931
2X-RAY DIFFRACTION2{ B|* }B577 - 931

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