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- PDB-6sd9: Crystal structure of wild-type cMET bound by foretinib -

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Basic information

Entry
Database: PDB / ID: 6sd9
TitleCrystal structure of wild-type cMET bound by foretinib
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE / Kinase / inhibitor
Function / homology
Function and homology information


negative regulation of guanyl-nucleotide exchange factor activity / hepatocyte growth factor receptor 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-plexin signaling pathway involved in axon guidance / semaphorin receptor activity ...negative regulation of guanyl-nucleotide exchange factor activity / hepatocyte growth factor receptor 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-plexin signaling pathway involved in axon guidance / semaphorin receptor activity / MET receptor recycling / semaphorin receptor complex / 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 / 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 / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator activity / Negative regulation of MET activity / neuron differentiation / receptor protein-tyrosine kinase / 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 / 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 / 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: 2.35 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
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)35,5103
Polymers34,8421
Non-polymers6682
Water99155
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area120 Å2
ΔGint-8 kcal/mol
Surface area12800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.880, 73.730, 91.470
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: 34842.320 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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: 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


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


Mass: 18.015 Da / Num. of mol.: 55 / 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: 2.34 Å3/Da / Density % sol: 47.54 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 15 % 2-propanol, 17 % 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: I02 / Wavelength: 0.97628 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97628 Å / Relative weight: 1
ReflectionResolution: 2.35→28.7 Å / Num. obs: 12096 / % possible obs: 97.5 % / Redundancy: 6.058 % / Biso Wilson estimate: 37.55 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.103 / Rrim(I) all: 0.113 / Χ2: 0.931 / Net I/σ(I): 13.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.35-2.494.790.4363.438009195116720.6080.48685.7
2.49-2.666.1430.355.0211193183418220.7720.38399.3
2.66-2.876.4570.2546.9311048171217110.9170.27799.9
2.87-3.146.4580.1869.3610294159415940.9680.202100
3.14-3.56.3770.13513.669285146014560.9860.14799.7
3.5-4.046.3750.08220.98205129012870.9950.0999.8
4.04-4.926.1850.06127.876810110211010.9970.06799.9
4.92-6.866.0640.0625.8354218968940.9970.06699.8
6.86-28.75.380.04331.3229865655550.9980.04898.2

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Processing

Software
NameVersionClassification
XSCALEdata scaling
BUSTER2.11.6refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LQ8

3lq8


Resolution: 2.35→28.7 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.852 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.393 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.412 / SU Rfree Blow DPI: 0.269 / SU Rfree Cruickshank DPI: 0.269
RfactorNum. reflection% reflectionSelection details
Rfree0.27 594 4.91 %RANDOM
Rwork0.21 ---
obs0.212 12096 98.2 %-
Displacement parametersBiso max: 118.19 Å2 / Biso mean: 42.38 Å2 / Biso min: 11.47 Å2
Baniso -1Baniso -2Baniso -3
1--3.7972 Å20 Å20 Å2
2---3.6538 Å20 Å2
3---7.451 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.35→28.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2063 0 47 55 2165
Biso mean--43.14 40.93 -
Num. residues----265
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d724SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes36HARMONIC2
X-RAY DIFFRACTIONt_gen_planes313HARMONIC5
X-RAY DIFFRACTIONt_it2164HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion273SEMIHARMONIC5
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_contact2535SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2164HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2939HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion2.79
X-RAY DIFFRACTIONt_other_torsion19.34
LS refinement shellResolution: 2.35→2.57 Å / Rfactor Rfree error: 0 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.277 123 4.66 %
Rwork0.243 2514 -
all0.245 2637 -
obs--92.4 %

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