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- PDB-5t3q: Crystal structure of the c-Met kinase domain in complex with a py... -

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Basic information

Entry
Database: PDB / ID: 5t3q
TitleCrystal structure of the c-Met kinase domain in complex with a pyrazolone inhibitor
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / phosphotransferase / cancer / inhibitor / 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 / 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-75H / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsBellon, S.F. / Whittington, D.A. / Long, A.M.
CitationJournal: to be published
Title: Discovery of AMG337: Using structure guided scaffold hydridization to optimize physicochemical properties and target coverage of a MET kinase inhibitor
Authors: Boezio, A.A. / Peterson, E.A. / Harmange, J.-C.
History
DepositionAug 26, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_prerelease_seq / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)35,7722
Polymers35,2161
Non-polymers5571
Water3,927218
1
A: Hepatocyte growth factor receptor
hetero molecules

A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,5454
Polymers70,4312
Non-polymers1,1132
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area1920 Å2
ΔGint-10 kcal/mol
Surface area25970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.627, 82.272, 127.139
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-1700-

HOH

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Components

#1: Protein Hepatocyte growth factor receptor / C-Met / 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: 35215.715 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Details: kinase domain / Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-75H / N-{3-fluoro-4-[(7-methoxyquinolin-4-yl)oxy]phenyl}-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide


Mass: 556.584 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H29FN4O5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 218 / 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: 2.66 Å3/Da / Density % sol: 53.75 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 12% PEG 6000, 1.0 M lithium chloride, 0.1 M sodium citrate (pH 5.0)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Dec 9, 2005 / Details: VariMax HR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→20 Å / Num. obs: 23885 / % possible obs: 92.6 % / Observed criterion σ(I): -3 / Redundancy: 2.9 % / Biso Wilson estimate: 36 Å2 / Rmerge(I) obs: 0.05 / Net I/av σ(I): 24.067 / Net I/σ(I): 25.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2-2.071.60.308161.5
2.07-2.1520.252183.6
2.15-2.252.80.213195.9
2.25-2.3730.162197.7
2.37-2.523.10.126198
2.52-2.713.10.091197.5
2.71-2.993.20.068198
2.99-3.423.30.05197.4
3.42-4.33.30.04197.6
4.3-203.30.036198

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.2data extraction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: proprietary cMet structure

Resolution: 2→20 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.937 / SU B: 4.47 / SU ML: 0.122 / SU R Cruickshank DPI: 0.1797 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.18 / ESU R Free: 0.171
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2482 1215 5.1 %RANDOM
Rwork0.1955 ---
obs0.1982 22650 92.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 99.8 Å2 / Biso mean: 30.923 Å2 / Biso min: 14.91 Å2
Baniso -1Baniso -2Baniso -3
1-0.86 Å20 Å20 Å2
2---0.66 Å20 Å2
3----0.2 Å2
Refinement stepCycle: final / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 41 218 2472
Biso mean--30.23 42.06 -
Num. residues----278
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.022313
X-RAY DIFFRACTIONr_bond_other_d0.0010.021554
X-RAY DIFFRACTIONr_angle_refined_deg1.2551.9813141
X-RAY DIFFRACTIONr_angle_other_deg0.8943.0023777
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.135275
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.41323.64696
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.56115394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.581511
X-RAY DIFFRACTIONr_chiral_restr0.0690.2351
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212502
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02457
LS refinement shellResolution: 1.999→2.051 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.404 45 -
Rwork0.389 999 -
all-1044 -
obs--57.36 %

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