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- PDB-3zze: Crystal structure of C-MET kinase domain in complex with N'-((3Z)... -

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Basic information

Entry
Database: PDB / ID: 3zze
TitleCrystal structure of C-MET kinase domain in complex with N'-((3Z)-4- chloro-7-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-(4- hydroxyphenyl)propanohydrazide
ComponentsHEPATOCYTE GROWTH FACTOR RECEPTOR
KeywordsTRANSFERASE / INHIBITOR
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 / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / liver development / molecular function activator activity / Negative regulation of MET activity / receptor protein-tyrosine kinase / 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 / Immunoglobulin E-set / Tyrosine protein kinases specific active-site signature. / 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-6XP / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsMcTigue, M. / Deng, Y. / Ryan, K. / Cui, J.J.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery of a Novel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor (C-met) Protein Kinase Inhibitors and Identification of the Clinical Candidate 2-(4-(1-(Quinolin-6- ...Title: Discovery of a Novel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor (C-met) Protein Kinase Inhibitors and Identification of the Clinical Candidate 2-(4-(1-(Quinolin-6-Ylmethyl)-1H-[1,2, 3]Triazolo[4,5-B]Pyrazin-6-Yl)-1H-Pyrazol-1-Yl)Ethanol (Pf-04217903) for the Treatment of Cancer.
Authors: Cui, J.J. / Mctigue, M. / Nambu, M. / Tran-Dube, M. / Pairish, M. / Shen, H. / Jia, L. / Cheng, H. / Hoffman, J. / Le, P. / Jalaie, M. / Goetz, G.H. / Ryan, K. / Grodsky, N. / Deng, Y. / ...Authors: Cui, J.J. / Mctigue, M. / Nambu, M. / Tran-Dube, M. / Pairish, M. / Shen, H. / Jia, L. / Cheng, H. / Hoffman, J. / Le, P. / Jalaie, M. / Goetz, G.H. / Ryan, K. / Grodsky, N. / Deng, Y. / Parker, M. / Timofeevski, S. / Murray, B.W. / Yamazaki, S. / Aguirre, S. / Li, Q. / Zou, H. / Christensen, J.
History
DepositionAug 31, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 14, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2012Group: Database references / Other / Structure summary
Revision 1.2Oct 10, 2012Group: Database references
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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)35,2392
Polymers34,8791
Non-polymers3601
Water4,234235
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)76.864, 94.373, 45.766
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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: 34879.414 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN, UNP RESIDUES 1051-1348
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC1 / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-6XP / (2S)-N'-[(3R)-4-chloro-7-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-hydroxyphenyl)propanehydrazide


Mass: 359.807 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18ClN3O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.38 Å3/Da / Density % sol: 48.31 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: CRYSTALS WERE OBTAINED AT 13 DEGREES C BY THE HANGING DROP VAPOR DIFFUSION METHOD USING 1.2 MICROLITERS OF PROTEIN SOLUTION (CONTAINING 7-13 MG/ML C-MET KD PLUS A 5 FOLD MOLAR EXCESS OF THE ...Details: CRYSTALS WERE OBTAINED AT 13 DEGREES C BY THE HANGING DROP VAPOR DIFFUSION METHOD USING 1.2 MICROLITERS OF PROTEIN SOLUTION (CONTAINING 7-13 MG/ML C-MET KD PLUS A 5 FOLD MOLAR EXCESS OF THE C-MET INHIBITOR COMPOUND) AND 1.2 MICROLITERS OF MOTHER LIQUOR SOLUTION (0.05 M CITRATE-PHOSHPHATE 4.6, 0-0.275 M NACL, AND 21% W/V PEG 3350).

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Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1
DetectorType: ADSC CCD / Detector: CCD / Date: Jan 29, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.74→50 Å / Num. obs: 28793 / % possible obs: 67.2 % / Observed criterion σ(I): 1 / Redundancy: 6 % / Biso Wilson estimate: 10.1 Å2 / Rmerge(I) obs: 0.12 / Net I/σ(I): 17
Reflection shellResolution: 1.87→1.96 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 1 / % possible all: 67.2

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Processing

Software
NameVersionClassification
CNS2005refinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WKM

2wkm


Resolution: 1.87→47.19 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 49707.01 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.226 723 2.9 %RANDOM
Rwork0.196 ---
obs0.196 24712 87.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 61.4235 Å2 / ksol: 0.395647 e/Å3
Displacement parametersBiso mean: 24.1 Å2
Baniso -1Baniso -2Baniso -3
1--7.08 Å20 Å20 Å2
2---5.09 Å20 Å2
3---12.17 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.23 Å0.19 Å
Luzzati d res low-5 Å
Luzzati sigma a0.15 Å0.17 Å
Refinement stepCycle: LAST / Resolution: 1.87→47.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2284 0 25 235 2544
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19.2
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.6
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.231.5
X-RAY DIFFRACTIONc_mcangle_it1.842
X-RAY DIFFRACTIONc_scbond_it2.262
X-RAY DIFFRACTIONc_scangle_it3.192.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.87→1.99 Å / Rfactor Rfree error: 0.031 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.268 77 2.8 %
Rwork0.232 2696 -
obs--59.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2DNA-RNA_REP.PARAMDNA-RNA.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP

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