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- PDB-6sdc: Crystal structure of D1228V cMET bound by foretinib -

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Basic information

Entry
Database: PDB / ID: 6sdc
TitleCrystal structure of D1228V cMET bound by foretinib
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / Kinase / 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 / 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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-88Z / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.67 Å
AuthorsCollie, G.W. / Phillips, C.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors.
Authors: Collie, G.W. / Koh, C.M. / O'Neill, D.J. / Stubbs, C.J. / Khurana, P. / Eddershaw, A. / Snijder, A. / Mauritzson, F. / Barlind, L. / Dale, I.L. / Shaw, J. / Phillips, C. / Hennessy, E.J. / ...Authors: Collie, G.W. / Koh, C.M. / O'Neill, D.J. / Stubbs, C.J. / Khurana, P. / Eddershaw, A. / Snijder, A. / Mauritzson, F. / Barlind, L. / Dale, I.L. / Shaw, J. / Phillips, C. / Hennessy, E.J. / Cheung, T. / Narvaez, A.J.
History
DepositionJul 26, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 14, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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)35,4592
Polymers34,8261
Non-polymers6331
Water5,080282
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.574, 80.396, 91.306
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 / 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: 34826.363 Da / Num. of mol.: 1
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-88Z / N-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide / Foretinib


Mass: 632.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H34F2N4O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 282 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.41 Å3/Da / Density % sol: 48.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 15 % 2-propanol, 10 % PEG4K, 0.1 M NaHEPES pH 8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 4, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.67→23.45 Å / Num. obs: 36878 / % possible obs: 99.3 % / Redundancy: 6.1 % / Biso Wilson estimate: 19.29 Å2 / CC1/2: 0.982 / Net I/σ(I): 6.3
Reflection shellResolution: 1.67→1.7 Å / Num. unique obs: 1669 / CC1/2: 0.443

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
DIALSdata scaling
PDB_EXTRACT3.25data extraction
DIALSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.67→23.45 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.918 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.105 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.112 / SU Rfree Blow DPI: 0.112 / SU Rfree Cruickshank DPI: 0.107
RfactorNum. reflection% reflectionSelection details
Rfree0.242 1829 4.98 %RANDOM
Rwork0.201 ---
obs0.203 36714 98.8 %-
Displacement parametersBiso max: 101.85 Å2 / Biso mean: 24.88 Å2 / Biso min: 7.21 Å2
Baniso -1Baniso -2Baniso -3
1-1.5484 Å20 Å20 Å2
2---5.2124 Å20 Å2
3---3.664 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: final / Resolution: 1.67→23.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2225 0 46 282 2553
Biso mean--22.66 34.27 -
Num. residues----286
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d794SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes39HARMONIC2
X-RAY DIFFRACTIONt_gen_planes343HARMONIC5
X-RAY DIFFRACTIONt_it2343HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion297SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2933SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2343HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3186HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3
X-RAY DIFFRACTIONt_other_torsion16.03
LS refinement shellResolution: 1.67→1.72 Å / Rfactor Rfree error: 0 / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.329 144 5.19 %
Rwork0.289 2632 -
all0.291 2776 -
obs--92.26 %

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