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- PDB-8ovz: Crystal structure of D1228V c-MET bound by compound 16 -

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Basic information

Entry
Database: PDB / ID: 8ovz
TitleCrystal structure of D1228V c-MET bound by compound 16
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / kinase / inhibitor / cancer research / drug discovery
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 / 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
Similarity search - Domain/homology
IODIDE ION / Chem-W3N / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.206 Å
AuthorsCollie, G.W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor.
Authors: Michaelides, I.N. / Collie, G.W. / Borjesson, U. / Vasalou, C. / Alkhatib, O. / Barlind, L. / Cheung, T. / Dale, I.L. / Embrey, K.J. / Hennessy, E.J. / Khurana, P. / Koh, C.M. / Lamb, M.L. / ...Authors: Michaelides, I.N. / Collie, G.W. / Borjesson, U. / Vasalou, C. / Alkhatib, O. / Barlind, L. / Cheung, T. / Dale, I.L. / Embrey, K.J. / Hennessy, E.J. / Khurana, P. / Koh, C.M. / Lamb, M.L. / Liu, J. / Moss, T.A. / O'Neill, D.J. / Phillips, C. / Shaw, J. / Snijder, A. / Storer, R.I. / Stubbs, C.J. / Han, F. / Li, C. / Qiao, J. / Sun, D.Q. / Wang, J. / Wang, P. / Yang, W.
History
DepositionApr 26, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Sep 20, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _pdbx_initial_refinement_model.type

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hepatocyte growth factor receptor
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,86123
Polymers69,6532
Non-polymers3,20821
Water3,081171
1
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,49412
Polymers34,8261
Non-polymers1,66711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,36711
Polymers34,8261
Non-polymers1,54110
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.9, 56.67, 215.81
Angle α, β, γ (deg.)90, 90, 90
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.: 2 / Mutation: D1228V
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-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 19 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-W3N / 1-[(1S)-1-[3-(1H-imidazol-4-yl)phenyl]ethyl]-5-(1H-indazol-7-yl)pyrimidine-2,4-dione


Mass: 398.417 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H18N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 171 / 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: 2.37 Å3/Da / Density % sol: 48.01 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 12 % PEG 8000, 200 mM NH4I, 0.1 M PCPT pH 7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 31, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.21→44.52 Å / Num. obs: 33771 / % possible obs: 98.8 % / Redundancy: 4.8 % / CC1/2: 0.992 / Net I/σ(I): 7.4
Reflection shellResolution: 2.21→2.26 Å / Num. unique obs: 2380 / CC1/2: 0.653

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.206→39.08 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.881 / SU R Cruickshank DPI: 0.283 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.29 / SU Rfree Blow DPI: 0.229 / SU Rfree Cruickshank DPI: 0.228
RfactorNum. reflection% reflectionSelection details
Rfree0.2749 1688 -RANDOM
Rwork0.2245 ---
obs0.227 33732 98.3 %-
Displacement parametersBiso mean: 41.47 Å2
Baniso -1Baniso -2Baniso -3
1-9.3102 Å20 Å20 Å2
2---9.0991 Å20 Å2
3----0.2112 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: LAST / Resolution: 2.206→39.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4518 0 79 171 4768
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0074701HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.876386HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1575SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes770HARMONIC5
X-RAY DIFFRACTIONt_it4701HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion596SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3609SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.81
X-RAY DIFFRACTIONt_other_torsion15.95
LS refinement shellResolution: 2.21→2.22 Å
RfactorNum. reflection% reflection
Rfree0.466 34 -
Rwork0.3295 --
obs0.336 675 86.75 %
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10-0.77160.86341.4961-2.11953.1475-0.06390.2337-0.32230.2337-0.0333-0.0343-0.3223-0.03430.0973-0.0332-0.0171-0.0165-0.01560.11190.021-4.09455.8091-39.2931
21.16610.16210.41330.1921-0.21970.93550.01920.0258-0.04110.0258-0.05590.073-0.04110.0730.0366-0.02660.01120.006-0.0375-0.026-0.0025-15.41981.3247-42.5521
32.7502-0.640.53740.75620.78950-0.10510.04880.04290.04880.12520.07490.04290.0749-0.020.0073-0.01940.0173-0.1053-0.00070.0276-22.0319.1151-37.8633
41.1471-0.30140.56140-0.5320.82850.21160.0178-0.0310.01780.0561-0.1177-0.031-0.1177-0.26770.0010.01060.0318-0.04080.00480.0188-35.62358.579-41.44
51.6637-0.5973-1.14960.19140.43190.84480.07410.05930.07790.05930.0113-0.22370.0779-0.2237-0.0854-0.0356-0.004-0.0353-0.04260.00560.0299-40.565-3.0829-44.2891
60.89130.81470.88720.53540.14470.7498-0.0446-0.071-0.099-0.0710.0882-0.1224-0.099-0.1224-0.0435-0.0328-0.00460.0449-0.04060.0860.0484-15.7524-13.7746-15.7985
71.139-0.7615-0.12880.23120.06090.6244-0.0382-0.03330.0162-0.03330.0882-0.0730.0162-0.073-0.05-0.041-0.0136-0.0036-0.04660.01060.0458-4.0788-19.6756-20.1304
81.6993-1.3038-0.45460.27431.32411.8872-0.1508-0.3357-0.1061-0.33570.2193-0.115-0.1061-0.115-0.0685-0.04840.0070.00890.00250.0065-0.03672.6181-14.316-12.4593
91.2901-0.39720.46560.2316-0.12260.71040.057-0.00840.0976-0.0084-0.0096-0.10280.0976-0.1028-0.0475-0.0362-0.00360.0075-0.0198-0.0180.023816.1508-18.1243-13.083
101.5670.56650.91361.03050.60290.3760.0943-0.15530.0935-0.1553-0.02940.21510.09350.2151-0.0649-0.00550.02990.0306-0.04710.02420.018721.0195-21.5729-24.5581
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|1061 - 1089}A1061 - 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
6X-RAY DIFFRACTION6{B|1057 - 1089}B1057 - 1089
7X-RAY DIFFRACTION7{B|1090 - 1213}B1090 - 1213
8X-RAY DIFFRACTION8{B|1214 - 1248}B1214 - 1248
9X-RAY DIFFRACTION9{B|1249 - 1295}B1249 - 1295
10X-RAY DIFFRACTION10{B|1296 - 1346}B1296 - 1346

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