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- PDB-8ov7: Crystal structure of D1228V c-MET bound by compound 10 -

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Basic information

Entry
Database: PDB / ID: 8ov7
TitleCrystal structure of D1228V c-MET bound by compound 10
ComponentsHepatocyte growth factor receptor
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 / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling ...hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / endothelial cell morphogenesis / semaphorin receptor activity / 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 / 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 / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / phagocytosis / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / liver development / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / molecular function activator activity / receptor protein-tyrosine kinase / Negative regulation of MET activity / neuron differentiation / 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 tyrosine kinase activity / protein phosphatase binding / postsynapse / receptor complex / cell surface receptor signaling pathway / 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 / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin E-set / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
Chem-W3W / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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 25, 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 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)35,2212
Polymers34,8261
Non-polymers3941
Water4,396244
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)111.645, 111.645, 130.432
Angle α, β, γ (deg.)90, 90, 90
Int Tables number92
Space group name H-MP41212

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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: 34826.363 Da / Num. of mol.: 1 / 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-W3W / 5-[3,5-bis(fluoranyl)phenyl]-1-[(1S)-1-[3-(1H-imidazol-5-yl)phenyl]ethyl]pyrimidine-2,4-dione


Mass: 394.374 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16F2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 244 / 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

Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.5 M LiCl, 0.1 M Na HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.95→78.94 Å / Num. obs: 60639 / % possible obs: 100 % / Redundancy: 12.5 % / CC1/2: 0.998 / Net I/σ(I): 9.6
Reflection shellResolution: 1.95→1.98 Å / Num. unique obs: 2948 / CC1/2: 0.512

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
DIALSdata reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→28.27 Å / Cor.coef. Fo:Fc: 0.898 / Cor.coef. Fo:Fc free: 0.899 / SU R Cruickshank DPI: 0.119 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.125 / SU Rfree Blow DPI: 0.118 / SU Rfree Cruickshank DPI: 0.114
RfactorNum. reflection% reflectionSelection details
Rfree0.287 3069 -RANDOM
Rwork0.273 ---
obs0.2737 60259 99.5 %-
Displacement parametersBiso mean: 33.82 Å2
Baniso -1Baniso -2Baniso -3
1-0.6096 Å20 Å20 Å2
2--0.6096 Å20 Å2
3----1.2192 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: LAST / Resolution: 1.95→28.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2240 0 29 244 2513
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082327HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.93165HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d767SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes380HARMONIC5
X-RAY DIFFRACTIONt_it2327HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion302SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2098SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.05
X-RAY DIFFRACTIONt_other_torsion15.29
LS refinement shellResolution: 1.95→1.96 Å
RfactorNum. reflection% reflection
Rfree0.4342 66 -
Rwork0.3711 --
obs0.3747 1206 97.48 %
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)
12.06270.84770.84031.11741.07130.74260.0094-0.0645-0.1401-0.06450.0344-0.0258-0.1401-0.0258-0.0438-0.0549-0.01620.01060.00710.1134-0.000130.932817.89947.531
20.44610.407-0.1531.5299-0.82990.46290.0174-0.08720.0535-0.08720.07580.01430.05350.0143-0.0932-0.0210.00610.0028-0.02650.0460.019129.51384.625712.7149
30.2998-0.36130.13873.3709-0.03111.1777-0.06210.1225-0.19310.12250.1897-0.1579-0.1931-0.1579-0.1276-0.01350.03490.0088-0.08270.05030.050725.67247.03822.7524
40.7160.3055-0.0581.1106-0.64090.963-0.02330.2106-0.19420.21060.1013-0.0574-0.1942-0.0574-0.0780.0210.05210.0209-0.05720.04950.040926.6086-1.355731.3274
50.46650.02940.27511.11670.27641.6250.01050.15190.0770.15190.02040.00730.0770.0073-0.031-0.00320.0329-0.0174-0.07660.05470.048631.5631-12.802729.0077
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|1059 - 1089}A1059 - 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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