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- PDB-4r1v: Identification and optimization of pyridazinones as potent and se... -

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Basic information

Entry
Database: PDB / ID: 4r1v
TitleIdentification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PROTEIN KINASE / Transferase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling ...hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling / pancreas development / MET activates PTPN11 / MET activates RAP1 and RAC1 / Sema4D mediated inhibition of cell attachment and migration / MET activates PI3K/AKT signaling / negative regulation of stress fiber assembly / positive regulation of endothelial cell chemotaxis / negative regulation of Rho protein signal transduction / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of thrombin-activated receptor signaling pathway / semaphorin-plexin signaling pathway / establishment of skin barrier / MET activates RAS signaling / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / phagocytosis / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / liver development / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / molecular function activator activity / receptor protein-tyrosine kinase / Negative regulation of MET activity / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / nervous system development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / postsynapse / receptor complex / cell surface receptor signaling pathway / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular region / ATP binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / IPT/TIG domain ...Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / IPT/TIG domain / ig-like, plexins, transcription factors / PSI domain / domain found in Plexins, Semaphorins and Integrins / IPT domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin E-set / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / WD40/YVTN repeat-like-containing 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-3E8 / GAMMA-BUTYROLACTONE / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.2 Å
AuthorsBlaukat, A. / Bladt, F. / Friese-Hamim, M. / Knuehl, C. / Fittschen, C. / Graedler, U. / Meyring, M. / Dorsch, D. / Stieber, F. / Schadt, O.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors.
Authors: Dorsch, D. / Schadt, O. / Stieber, F. / Meyring, M. / Gradler, U. / Bladt, F. / Friese-Hamim, M. / Knuhl, C. / Pehl, U. / Blaukat, A.
History
DepositionAug 7, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2015Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7425
Polymers32,9911
Non-polymers7514
Water6,287349
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.000, 43.038, 84.844
Angle α, β, γ (deg.)90.00, 92.23, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Hepatocyte growth factor receptor / HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / ...HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / Tyrosine-protein kinase Met


Mass: 32991.375 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP residues 1055-1345
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-3E8 / 3-[1-(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile


Mass: 492.572 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H28N6O2
#3: Chemical ChemComp-GBL / GAMMA-BUTYROLACTONE / DIHYDROFURAN-2(3H)-ONE


Mass: 86.089 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 349 / Source method: isolated from a natural source / Formula: H2O

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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: 2.12 Å3/Da / Density % sol: 41.95 % / Description: NONE
Crystal growTemperature: 298 K / pH: 6.5
Details: PEG 8000, pH 6.5, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.9999
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: May 24, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.2→84.82 Å / Num. obs: 85595 / % possible obs: 97.3 % / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Rmerge(I) obs: 0.038
Reflection shellResolution: 1.2→1.23 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.41 / % possible all: 72.3

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Processing

Software
NameVersionClassification
XDSdata scaling
PHASESphasing
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementResolution: 1.2→84.82 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.97 / SU B: 1.382 / SU ML: 0.027 / Cross valid method: THROUGHOUT / ESU R: 0.039 / ESU R Free: 0.039 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.176 1654 2 %RANDOM
Rwork0.146 ---
obs0.146 81815 97.5 %-
all-85595 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 14.37 Å2
Baniso -1Baniso -2Baniso -3
1--0.12 Å20 Å2-0.08 Å2
2--0.11 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.2→84.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2305 0 55 349 2709
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222490
X-RAY DIFFRACTIONr_bond_other_d0.0010.022284
X-RAY DIFFRACTIONr_angle_refined_deg1.3931.9863379
X-RAY DIFFRACTIONr_angle_other_deg0.81935325
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6425303
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.38623.333102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.06115431
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5171514
X-RAY DIFFRACTIONr_chiral_restr0.0880.2370
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022734
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02513
X-RAY DIFFRACTIONr_nbd_refined0.2210.2523
X-RAY DIFFRACTIONr_nbd_other0.1730.22324
X-RAY DIFFRACTIONr_nbtor_refined0.1840.21240
X-RAY DIFFRACTIONr_nbtor_other0.0840.21337
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.2206
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2020.211
X-RAY DIFFRACTIONr_symmetry_vdw_other0.290.288
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1880.243
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.21421937
X-RAY DIFFRACTIONr_mcbond_other1.5652605
X-RAY DIFFRACTIONr_mcangle_it3.78932444
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.69341174
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.6016935
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr2.38535811
X-RAY DIFFRACTIONr_sphericity_free12.0393349
X-RAY DIFFRACTIONr_sphericity_bonded5.49734705
LS refinement shellResolution: 1.2→1.23 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.283 89 -
Rwork0.261 4661 -
obs--75.25 %

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