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- PDB-2wd1: Human c-Met Kinase in complex with azaindole inhibitor -

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Basic information

Entry
Database: PDB / ID: 2wd1
TitleHuman c-Met Kinase in complex with azaindole inhibitor
ComponentsHEPATOCYTE GROWTH FACTOR RECEPTOR
KeywordsTRANSFERASE / HUMAN KINASE / C-MET / AZAINDOLE / INHIBITOR / KINASE / NUCLEOTIDE-BINDING / ATP-BINDING / TYROSINE-PROTEIN KINASE
Function / homology
Function and homology information


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 Receptor Activation / MET interacts with TNS proteins / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling / pancreas development ...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 Receptor Activation / MET interacts with TNS proteins / 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 / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of Rho protein signal transduction / 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 / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / cell surface receptor protein tyrosine kinase signaling pathway / liver development / molecular function activator activity / InlB-mediated entry of Listeria monocytogenes into host cell / basal plasma membrane / excitatory postsynaptic potential / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / Negative regulation of MET activity / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein phosphatase binding / receptor complex / cell surface receptor signaling pathway / postsynapse / 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 / IPT domain / PSI domain / domain found in Plexins, Semaphorins and Integrins / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Immunoglobulin E-set / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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
GAMMA-BUTYROLACTONE / Chem-ZZY / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsPorter, J. / Lumb, S. / Franklin, R.J. / Gascon-Simorte, J.M. / Calmiano, M. / Le Riche, K. / Lallemand, B. / Keyaerts, J. / Edwards, H. / Maloney, A. ...Porter, J. / Lumb, S. / Franklin, R.J. / Gascon-Simorte, J.M. / Calmiano, M. / Le Riche, K. / Lallemand, B. / Keyaerts, J. / Edwards, H. / Maloney, A. / Delgado, J. / King, L. / Foley, A. / Lecomte, F. / Reuberson, J. / Meier, C. / Batchelor, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Discovery of 4-Azaindoles as Novel Inhibitors of C- met Kinase.
Authors: Porter, J. / Lumb, S. / Franklin, R.J. / Gascon-Simorte, J.M. / Calmiano, M. / Riche, K.L. / Lallemand, B. / Keyaerts, J. / Edwards, H. / Maloney, A. / Delgado, J. / King, L. / Foley, A. / ...Authors: Porter, J. / Lumb, S. / Franklin, R.J. / Gascon-Simorte, J.M. / Calmiano, M. / Riche, K.L. / Lallemand, B. / Keyaerts, J. / Edwards, H. / Maloney, A. / Delgado, J. / King, L. / Foley, A. / Lecomte, F. / Reuberson, J. / Meier, C. / Batchelor, M.
History
DepositionMar 19, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 28, 2009Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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)33,5674
Polymers33,0481
Non-polymers5183
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)37.411, 42.312, 84.826
Angle α, β, γ (deg.)90.00, 93.01, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein HEPATOCYTE GROWTH FACTOR RECEPTOR / SCATTER FACTOR RECEPTOR / HGF/SF RECEPTOR / MET PROTO-ONCOGENE TYROSINE KINASE / C-MET


Mass: 33048.426 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 1055-1346
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-ZZY / 1-[(2-NITROPHENYL)SULFONYL]-1H-PYRROLO[3,2-B]PYRIDINE-6-CARBOXAMIDE


Mass: 346.318 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H10N4O5S
#3: Chemical ChemComp-GBL / GAMMA-BUTYROLACTONE / DIHYDROFURAN-2(3H)-ONE


Mass: 86.089 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE CONFLICT DESCRIBED IN THE SEQADV RECORDS BELOW IS ANNOTATED IN THE UNIPROT DATABASE AND HAS ...THE CONFLICT DESCRIBED IN THE SEQADV RECORDS BELOW IS ANNOTATED IN THE UNIPROT DATABASE AND HAS BEEN DESCRIBED IN PUBMED ID: 12853948 AND 3325883.

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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: 1.98 Å3/Da / Density % sol: 39 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 1, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→42.37 Å / Num. obs: 18000 / % possible obs: 99.1 % / Observed criterion σ(I): 2 / Redundancy: 4 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 12.43
Reflection shellResolution: 2→2.1 Å / Redundancy: 4 % / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 4.22 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→42.37 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.881 / SU B: 6.152 / SU ML: 0.167 / Cross valid method: THROUGHOUT / ESU R: 0.241 / ESU R Free: 0.202 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.265 774 4.3 %RANDOM
Rwork0.21 ---
obs0.212 17224 100 %-
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: 20.436 Å2
Refinement stepCycle: LAST / Resolution: 2→42.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2303 0 36 71 2410
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222408
X-RAY DIFFRACTIONr_bond_other_d0.0010.022195
X-RAY DIFFRACTIONr_angle_refined_deg1.1481.9763270
X-RAY DIFFRACTIONr_angle_other_deg0.77935098
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9255295
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.67523.16398
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.11115405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6951513
X-RAY DIFFRACTIONr_chiral_restr0.0690.2360
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022659
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02498
X-RAY DIFFRACTIONr_nbd_refined0.1970.2490
X-RAY DIFFRACTIONr_nbd_other0.1790.22163
X-RAY DIFFRACTIONr_nbtor_refined0.1770.21193
X-RAY DIFFRACTIONr_nbtor_other0.0830.21247
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1670.293
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1570.218
X-RAY DIFFRACTIONr_symmetry_vdw_other0.220.291
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1290.28
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.39921902
X-RAY DIFFRACTIONr_mcbond_other0.542596
X-RAY DIFFRACTIONr_mcangle_it2.89732382
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.07941116
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.0646888
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→2.05 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.345 55 -
Rwork0.271 1243 -
obs--100 %

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