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- PDB-7zy6: Identification of M4205 a highly selective inhibitor of cKIT muta... -

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Basic information

Entry
Database: PDB / ID: 7zy6
TitleIdentification of M4205 a highly selective inhibitor of cKIT mutations for unresectable metastatic or recurrent GIST
ComponentsHUMAN PROTO-ONCOGENE C-KIT
KeywordsTRANSFERASE / TYROSINE-PROTEIN KINASE / cKIT
Function / homologyPhosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta / Chem-KCI
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.09 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 24, 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

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Assembly

Deposited unit
A: HUMAN PROTO-ONCOGENE C-KIT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5622
Polymers37,1781
Non-polymers3841
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.944, 78.806, 97.039
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 HUMAN PROTO-ONCOGENE C-KIT


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) / Production host: Spodoptera frugiperda (fall armyworm)
#2: Chemical ChemComp-KCI / 5-imidazo[1,2-a]pyridin-3-yl-~{N}-[(1~{R})-1-(6-pyrrolidin-1-ylpyridin-3-yl)ethyl]pyridin-3-amine


Mass: 384.477 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24N6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.47 Å3/Da / Density % sol: 47.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 8 / Details: 5.0% PEG8000, 0.1M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99993 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99993 Å / Relative weight: 1
ReflectionResolution: 3.09→61.17 Å / Num. obs: 6583 / % possible obs: 96 % / Redundancy: 2.8 % / Biso Wilson estimate: 131.06 Å2 / Rrim(I) all: 0.034 / Rsym value: 0.028 / Net I/σ(I): 24.78
Reflection shellResolution: 3.09→3.34 Å / Redundancy: 2.7 % / Mean I/σ(I) obs: 2.33 / Num. unique obs: 1361 / Rrim(I) all: 0.581 / Rsym value: 0.472 / % possible all: 98.5

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (3-FEB-2022)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3G0E

3g0e


Resolution: 3.09→41.52 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.902 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.554
RfactorNum. reflection% reflectionSelection details
Rfree0.2977 501 7.61 %RANDOM
Rwork0.22 ---
obs0.2257 6583 96 %-
Displacement parametersBiso max: 190.68 Å2 / Biso mean: 131.62 Å2 / Biso min: 61.66 Å2
Baniso -1Baniso -2Baniso -3
1--17.7661 Å20 Å20 Å2
2--8.0236 Å20 Å2
3---9.7426 Å2
Refine analyzeLuzzati coordinate error obs: 0.44 Å
Refinement stepCycle: final / Resolution: 3.09→41.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2330 0 29 1 2360
Biso mean--87.27 61.66 -
Num. residues----293
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d837SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes395HARMONIC5
X-RAY DIFFRACTIONt_it2418HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion305SEMIHARMONIC5
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_contact1936SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2418HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3269HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion2.67
X-RAY DIFFRACTIONt_other_torsion20.66
LS refinement shellResolution: 3.09→3.13 Å / Rfactor Rfree error: 0 / Total num. of bins used: 26
RfactorNum. reflection% reflection
Rfree0.3454 15 5.68 %
Rwork0.3516 249 -
all0.3513 264 -
obs--98.15 %
Refinement TLS params.Method: refined / Origin x: 15.1828 Å / Origin y: 5.5676 Å / Origin z: -21.7697 Å
111213212223313233
T-0.2759 Å20.1288 Å2-0.1469 Å2-0.0419 Å2-0.1383 Å2---0.1849 Å2
L5.4936 °2-0.4924 °2-0.3195 °2-0.7748 °22.9104 °2--8.3154 °2
S0.223 Å °0.5186 Å °-0.5442 Å °0.5167 Å °0.0982 Å °0.1139 Å °0.44 Å °0.2688 Å °-0.3212 Å °
Refinement TLS groupSelection details: { A|* }

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