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- PDB-6sde: Crystal structure of wild-type cMET bound by savolitinib -

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Basic information

Entry
Database: PDB / ID: 6sde
TitleCrystal structure of wild-type cMET bound by savolitinib
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / Kinase / inhibitor
Function / homology
Function and homology information


hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity ...hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity / MET receptor recycling / Sema4D mediated inhibition of cell attachment and migration / pancreas development / MET activates PTPN11 / negative regulation of Rho protein signal transduction / MET activates RAP1 and RAC1 / MET activates PI3K/AKT signaling / negative regulation of stress fiber assembly / negative regulation of thrombin-activated receptor signaling pathway / semaphorin-plexin signaling pathway / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / establishment of skin barrier / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / MET activates RAS signaling / phagocytosis / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / Negative regulation of MET activity / neuron differentiation / receptor protein-tyrosine kinase / transmembrane receptor protein tyrosine kinase activity / positive regulation of kinase activity / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / nervous system development / transmembrane receptor protein tyrosine kinase signaling pathway / cell migration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of protein kinase B signaling / protein phosphatase binding / cell surface receptor signaling pathway / receptor complex / cell surface / signal transduction / plasma membrane => GO:0005886 / positive regulation of transcription by RNA polymerase II / extracellular region / membrane => GO:0016020 / ATP binding / 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 profile. / Sema domain superfamily / IPT/TIG domain ...Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain profile. / Sema domain superfamily / IPT/TIG domain / ig-like, plexins, transcription factors / domain found in Plexins, Semaphorins and Integrins / PSI domain / 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 / WD40/YVTN repeat-like-containing domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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
volitinib / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.49 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)35,1882
Polymers34,8421
Non-polymers3451
Water1,00956
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 area12930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.130, 43.360, 156.410
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: 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-V0L / volitinib / Savolitinib


Mass: 345.361 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N9 / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 56 / 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: 47.34 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 15 % 2-propanol, 15 % PEG4K, 0.2 M PCPT pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.98003 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98003 Å / Relative weight: 1
ReflectionResolution: 2.49→43.36 Å / Num. obs: 10493 / % possible obs: 99.1 % / Redundancy: 6.5 % / CC1/2: 0.997 / Net I/σ(I): 8.8
Reflection shellResolution: 2.49→2.56 Å / Num. unique obs: 718 / CC1/2: 0.427

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2WGJ
Resolution: 2.49→41.78 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.849 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.598 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.721 / SU Rfree Blow DPI: 0.317 / SU Rfree Cruickshank DPI: 0.314
RfactorNum. reflection% reflectionSelection details
Rfree0.273 523 5 %RANDOM
Rwork0.203 ---
obs0.206 10450 98.3 %-
Displacement parametersBiso max: 161 Å2 / Biso mean: 69.55 Å2 / Biso min: 34.86 Å2
Baniso -1Baniso -2Baniso -3
1-5.9805 Å20 Å20 Å2
2---10.4144 Å20 Å2
3---4.4339 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: final / Resolution: 2.49→41.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2133 0 26 56 2215
Biso mean--61.84 60.59 -
Num. residues----268
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d745SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes39HARMONIC2
X-RAY DIFFRACTIONt_gen_planes319HARMONIC5
X-RAY DIFFRACTIONt_it2217HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion278SEMIHARMONIC5
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_contact2536SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2217HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3005HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion2.73
X-RAY DIFFRACTIONt_other_torsion18.83
LS refinement shellResolution: 2.49→2.78 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.278 142 5.01 %
Rwork0.204 2694 -
all0.207 2836 -
obs--96.14 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
12.8682-0.1399-2.04481.9779-0.70893.5460.01360.01830.0186-0.09680.0250.0453-0.12490.0183-0.03860.21550.1520.0424-0.10150.0968-0.148416.087236.853847.8598
21.3414-0.18710.11161.7016-0.52492.16740.16950.33620.1144-0.4549-0.0110.0812-0.5163-0.323-0.1585-0.00980.1320.0175-0.03180.0825-0.109517.627727.067257.4252
31.2567-0.67772.38961.727-0.90542.53270.01560.29720.1673-0.369-0.1434-0.1094-0.21710.44740.1278-0.02120.08310.10630.05750.0839-0.135528.139924.173256.4139
44.3456-0.64190.89392.1682-0.30632.43670.05570.2960.0434-0.2763-0.1421-0.0531-0.01710.28910.0864-0.0590.01220.04350.01620.0658-0.027934.101216.135763.9666
53.7359-1.4498-0.53531.2830.40361.77960.02360.1407-0.11490.0245-0.00710.07220.20620.0327-0.0165-0.08540.0088-0.0089-0.0320.0198-0.012427.413512.044574.2444
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|1053 - 1089}A1053 - 1089
2X-RAY DIFFRACTION2{A|1090 - 1213}A1090 - 1213
3X-RAY DIFFRACTION3{A|1214 - 1248}A1214 - 1248
4X-RAY DIFFRACTION4{A|1249 - 1295}A1249 - 1295
5X-RAY DIFFRACTION5{A|1296 - 1346}A1296 - 1346

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