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- PDB-7zw8: Identification of M4205 a highly selective inhibitor of cKIT muta... -

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Basic information

Entry
Database: PDB / ID: 7zw8
TitleIdentification of M4205 a highly selective inhibitor of cKIT mutations for unresectable metastatic or recurrent GIST
ComponentsMast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE / TYROSINE-PROTEIN KINASE / cKIT
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 / 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-K3R / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.119 Å
AuthorsGraedler, U. / Lammens, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Identification of M4205─A Highly Selective Inhibitor of KIT Mutations for Treatment of Unresectable Metastatic or Recurrent Gastrointestinal Stromal Tumors.
Authors: Blum, A. / Dorsch, D. / Linde, N. / Brandstetter, S. / Buchstaller, H.P. / Busch, M. / Glaser, N. / Gradler, U. / Ruff, A. / Petersson, C. / Schieferstein, H. / Sherbetjian, E. / Esdar, C.
History
DepositionMay 19, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)37,6872
Polymers37,1781
Non-polymers5091
Water72140
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.056, 81.307, 96.049
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 / 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: 37177.957 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-K3R / ~{N}-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]-6-[7-(3-pyrrolidin-1-ylpropoxy)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-amine / [4-(1-Methyl-1H-pyrazol-4-yl)-benzyl]-{6-[7-(3-pyrrolidin-1-yl-propoxy)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-4-yl}-amine


Mass: 508.617 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H32N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 40 / 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: 2.48 Å3/Da / Density % sol: 50.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.25 / Details: 9% (w/v) PEG 8K, 0.1 M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.000067 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 3, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.000067 Å / Relative weight: 1
ReflectionResolution: 2.119→48.025 Å / Num. obs: 13325 / % possible obs: 92.6 % / Redundancy: 7.7 % / Biso Wilson estimate: 66.28 Å2 / CC1/2: 1 / Rpim(I) all: 0.018 / Rrim(I) all: 0.049 / Rsym value: 0.046 / Net I/σ(I): 19.3
Reflection shellResolution: 2.119→2.41 Å / Redundancy: 4.4 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 666 / CC1/2: 0.804 / Rpim(I) all: 0.458 / Rrim(I) all: 0.996 / Rsym value: 0.879 / % possible all: 62.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (3-FEB-2022)refinement
XDSVERSION Jan 31, 2020data reduction
STARANISOdata scaling
MOLREPphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3g0e

3g0e


Resolution: 2.119→48.02 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.935 / SU R Cruickshank DPI: 0.44 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.449 / SU Rfree Blow DPI: 0.264 / SU Rfree Cruickshank DPI: 0.266
RfactorNum. reflection% reflectionSelection details
Rfree0.2498 988 7.41 %RANDOM
Rwork0.2087 ---
obs0.2118 13325 62.9 %-
Displacement parametersBiso max: 140.22 Å2 / Biso mean: 76.56 Å2 / Biso min: 44.21 Å2
Baniso -1Baniso -2Baniso -3
1--0.5252 Å20 Å20 Å2
2---1.8052 Å20 Å2
3---2.3304 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 2.119→48.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2399 0 38 40 2477
Biso mean--56.95 65.22 -
Num. residues----301
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d870SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes410HARMONIC5
X-RAY DIFFRACTIONt_it2505HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion315SEMIHARMONIC5
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_contact1911SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2505HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg3389HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion17.43
LS refinement shellResolution: 2.12→2.3 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.4351 16 5.88 %
Rwork0.3373 256 -
all0.3425 272 -
obs--5.86 %
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)
14.70810.1672-1.72214.74310.44793.31660.2005-0.43270.21170.3058-0.20740.133-0.122-0.08280.0069-0.0229-0.0145-0.0085-0.0743-0.0422-0.091311.68814.6891-9.9217
23.2496-1.2328-1.16715.0932.23263.18120.23660.2925-0.4942-0.4362-0.1755-0.4528-0.2918-0.2443-0.0611-0.0794-0.0006-0.0215-0.0828-0.07710.017319.03152.6151-29.6598
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|553 - A|672 }A553 - 672
2X-RAY DIFFRACTION2{ A|673 - A|932 }A673 - 932

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