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- PDB-8ouu: Crystal structure of D1228V c-MET bound by compound 29 -

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Basic information

Entry
Database: PDB / ID: 8ouu
TitleCrystal structure of D1228V c-MET bound by compound 29
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
FORMIC ACID / Chem-W49 / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.77 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 24, 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

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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)70,81811
Polymers69,6532
Non-polymers1,1659
Water7,764431
1
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4015
Polymers34,8261
Non-polymers5754
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4176
Polymers34,8261
Non-polymers5915
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.626, 56.738, 214.771
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 5 types, 440 molecules

#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: CH2O2
#5: Chemical ChemComp-W49 / 5-(3-ethynyl-5-fluoranyl-1H-indazol-7-yl)-1-[(1S)-1-phenylethyl]pyrimidine-2,4-dione


Mass: 374.368 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H15FN4O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 431 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.35 Å3/Da / Density % sol: 47.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 2 M Na formate, 0.1 M Na acetate pH 4.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.91589 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91589 Å / Relative weight: 1
ReflectionResolution: 1.77→71.59 Å / Num. obs: 64902 / % possible obs: 99.9 % / Redundancy: 6.1 % / CC1/2: 0.998 / Net I/σ(I): 9.5
Reflection shellResolution: 1.77→1.8 Å / Num. unique obs: 3094 / CC1/2: 0.729

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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: 1.77→54.86 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.919 / SU R Cruickshank DPI: 0.12 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.126 / SU Rfree Blow DPI: 0.114 / SU Rfree Cruickshank DPI: 0.111
RfactorNum. reflection% reflectionSelection details
Rfree0.2251 3122 -RANDOM
Rwork0.2021 ---
obs0.2033 64804 99.7 %-
Displacement parametersBiso mean: 33.47 Å2
Baniso -1Baniso -2Baniso -3
1-12.4455 Å20 Å20 Å2
2---14.3229 Å20 Å2
3---1.8773 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: LAST / Resolution: 1.77→54.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4520 0 83 431 5034
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0094753HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.916453HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1601SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes787HARMONIC5
X-RAY DIFFRACTIONt_it4753HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion599SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4585SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.09
X-RAY DIFFRACTIONt_other_torsion15.38
LS refinement shellResolution: 1.77→1.78 Å
RfactorNum. reflection% reflection
Rfree0.4306 63 -
Rwork0.306 --
obs0.312 1297 95.21 %

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