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- PDB-2wgj: X-ray Structure of PF-02341066 bound to the kinase domain of c-Met -

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Basic information

Entry
Database: PDB / ID: 2wgj
TitleX-ray Structure of PF-02341066 bound to the kinase domain of c-Met
ComponentsHEPATOCYTE GROWTH FACTOR RECEPTORC-Met
KeywordsTRANSFERASE / C-MET / KINASE / INHIBITOR / ATP-BINDING / NUCLEOTIDE-BINDING / TYROSINE-PROTEIN KINASE
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 / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / semaphorin receptor activity / positive regulation of endothelial cell chemotaxis ...hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / semaphorin receptor activity / positive regulation of endothelial cell chemotaxis / 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 / 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 / phagocytosis / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / basal plasma membrane / negative regulation of autophagy / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator activity / Negative regulation of MET activity / receptor protein-tyrosine kinase / neuron differentiation / cell surface receptor protein tyrosine kinase signaling pathway / 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 phosphatase binding / protein tyrosine kinase activity / cell surface receptor signaling pathway / receptor complex / phosphorylation / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular region / ATP binding / membrane / identical protein binding / 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 / Immunoglobulin E-set / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-VGH / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsMcTigue, M. / Grodsky, N. / Ryan, K. / Tran-Dube, M. / Cui, J.J. / Mroczkowski, B.
CitationJournal: J.Med.Chem / Year: 2011
Title: Structure Based Drug Design of Crizotinib (Pf-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (C-met) Kinase and Anaplastic Lymphoma Kinase (Alk).
Authors: Cui, J.J. / Tran-Dube, M. / Shen, H. / Nambu, M. / Kung, P.P. / Pairish, M. / Jia, L. / Meng, J. / Funk, L. / Botrous, I. / Mctigue, M. / Grodsky, N. / Ryan, K. / Padrique, E. / Alton, G. / ...Authors: Cui, J.J. / Tran-Dube, M. / Shen, H. / Nambu, M. / Kung, P.P. / Pairish, M. / Jia, L. / Meng, J. / Funk, L. / Botrous, I. / Mctigue, M. / Grodsky, N. / Ryan, K. / Padrique, E. / Alton, G. / Timofeevski, S. / Yamazaki, S. / Li, Q. / Zou, H. / Christensen, J. / Mroczkowski, B. / Bender, S. / Kania, R.S. / Edwards, M.P.
History
DepositionApr 20, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 2, 2009Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2011Group: Database references / Non-polymer description ...Database references / Non-polymer description / Structure summary / Version format compliance
Revision 1.2May 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 1.3Dec 13, 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

Downloads & links

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Assembly

Deposited unit
A: HEPATOCYTE GROWTH FACTOR RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3302
Polymers34,8791
Non-polymers4501
Water3,243180
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)76.926, 94.192, 45.990
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 / C-Met / HGF RECEPTOR / SCATTER FACTOR RECEPTOR / SF RECEPTOR / HGF/SF RECEPTOR / MET PROTO-ONCOGENE ...HGF RECEPTOR / SCATTER FACTOR RECEPTOR / SF RECEPTOR / HGF/SF RECEPTOR / MET PROTO-ONCOGENE TYROSINE KINASE / C-MET


Mass: 34879.414 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN, 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-VGH / 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-amine / CRIZOTINIB / Crizotinib


Mass: 450.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22Cl2FN5O / Comment: medication, anticancer, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 2.36 Å3/Da / Density % sol: 47.5 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: CRYSTALS WERE GROWN BY HANGING DROP VAPOR DIFFUSION AT 13 DEGREES CELCIUS. 1-2 MICROLITERS OF PROTEIN SOLUTION AT 7-15 MG/ML WAS MIXEDWITH AN EQUAL VOLUME OF PRECIPITATING SOLUTION (0-275 MM ...Details: CRYSTALS WERE GROWN BY HANGING DROP VAPOR DIFFUSION AT 13 DEGREES CELCIUS. 1-2 MICROLITERS OF PROTEIN SOLUTION AT 7-15 MG/ML WAS MIXEDWITH AN EQUAL VOLUME OF PRECIPITATING SOLUTION (0-275 MM SODIUM CHLORIDE, 21% (W/V PEG 3350, 50 MM CITRATE-PHOSPHATE PH 4.6)

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1
DetectorType: ADSC CCD / Detector: CCD / Date: Apr 30, 2006 / Details: PINHOLE COLLIMATOR
RadiationMonochromator: DOUBLE CRYSTAL SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 18192 / % possible obs: 78.1 % / Observed criterion σ(I): 1 / Redundancy: 3.9 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 20
Reflection shellResolution: 2→2.05 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.29 / Mean I/σ(I) obs: 2.5 / % possible all: 38.5

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3LCK

3lck


Resolution: 2→19.96 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.932 / SU B: 5.681 / SU ML: 0.145 / Cross valid method: THROUGHOUT / ESU R: 0.282 / ESU R Free: 0.196 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23153 926 5.1 %RANDOM
Rwork0.21396 ---
obs0.21485 17195 78.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 40.859 Å2
Baniso -1Baniso -2Baniso -3
1--2.06 Å20 Å20 Å2
2---4.32 Å20 Å2
3---6.38 Å2
Refinement stepCycle: LAST / Resolution: 2→19.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2309 0 30 180 2519
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0212400
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0811.9713251
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1485287
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0760.2361
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021784
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1930.21117
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1410.2140
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.170.246
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2130.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5721.51441
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.08622338
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.3863959
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.3474.5913
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.221 33 -
Rwork0.265 593 -
obs--38.5 %

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