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- PDB-4eev: Crystal structure of c-Met in complex with LY2801653 -

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Basic information

Entry
Database: PDB / ID: 4eev
TitleCrystal structure of c-Met in complex with LY2801653
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein tyrosine kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
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
Chem-L1X / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsWang, Y. / Stout, S.L.
CitationJournal: Invest New Drugs / Year: 2013
Title: LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models.
Authors: Yan, S.B. / Peek, V.L. / Ajamie, R. / Buchanan, S.G. / Graff, J.R. / Heidler, S.A. / Hui, Y.H. / Huss, K.L. / Konicek, B.W. / Manro, J.R. / Shih, C. / Stewart, J.A. / Stewart, T.R. / Stout, ...Authors: Yan, S.B. / Peek, V.L. / Ajamie, R. / Buchanan, S.G. / Graff, J.R. / Heidler, S.A. / Hui, Y.H. / Huss, K.L. / Konicek, B.W. / Manro, J.R. / Shih, C. / Stewart, J.A. / Stewart, T.R. / Stout, S.L. / Uhlik, M.T. / Um, S.L. / Wang, Y. / Wu, W. / Yan, L. / Yang, W.J. / Zhong, B. / Walgren, R.A.
History
DepositionMar 28, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 10, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2013Group: 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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)36,4862
Polymers35,9341
Non-polymers5531
Water2,252125
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.508, 63.886, 111.631
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 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: 35933.578 Da / Num. of mol.: 1 / Fragment: kinase domain (unp residues 1038-1346)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Escherichia coli (E. coli)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-L1X / N-(3-fluoro-4-{[1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl]oxy}phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide


Mass: 552.531 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H22F2N6O3 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.01 Å3/Da / Density % sol: 38.8 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 16% PEG 10.000, 0.1 M HEPES, and 5% ethylene glycol, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID
DetectorType: RAYONIX MX225HE / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.511→19.94 Å / Num. all: 46378 / Num. obs: 45914 / % possible obs: 99 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 9.4 % / Biso Wilson estimate: 28 Å2 / Rmerge(I) obs: 0.086 / Rsym value: 0.086 / Net I/σ(I): 10.1
Reflection shell

Rmerge(I) obs: 0.06 / Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.51-1.598.50.15321262586.01794.2
1.59-1.699.60.36088663322.29999.7
1.69-1.89.70.55714959171.25399.8
1.8-1.959.61.35369755690.54799.9
1.95-2.139.734960251220.23999.9
2.13-2.399.75.64512346730.129100
2.39-2.769.68.23990941360.082100
2.76-3.389.6103398335560.058100
3.38-4.779.312.32571927650.04899.8
4.77-19.9298.412.81334815860.04597

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Processing

Software
NameVersionClassificationNB
SCALA2.7.2data scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
MAR345dtbdata collection
MOSFLMdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→19.94 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.955 / WRfactor Rfree: 0.2404 / WRfactor Rwork: 0.2049 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8562 / SU B: 2.757 / SU ML: 0.086 / SU R Cruickshank DPI: 0.132 / SU Rfree: 0.1197 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.132 / ESU R Free: 0.12 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2153 1388 5 %RANDOM
Rwork0.1889 ---
all0.1903 27636 --
obs0.1903 27552 99.7 %-
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 max: 90.56 Å2 / Biso mean: 37.2593 Å2 / Biso min: 19.71 Å2
Baniso -1Baniso -2Baniso -3
1-1.75 Å20 Å20 Å2
2--0.48 Å20 Å2
3----2.23 Å2
Refinement stepCycle: LAST / Resolution: 1.8→19.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2206 0 41 125 2372
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0192346
X-RAY DIFFRACTIONr_bond_other_d0.0060.021555
X-RAY DIFFRACTIONr_angle_refined_deg1.5881.9863198
X-RAY DIFFRACTIONr_angle_other_deg0.97333817
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1935293
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.66823.59689
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.69615394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9981510
X-RAY DIFFRACTIONr_chiral_restr0.0990.2361
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212644
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02463
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.281 97 -
Rwork0.234 1924 -
all-2021 -
obs--99.85 %

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