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- PDB-7b41: Crystal structure of c-MET bound by compound 7 -

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Basic information

Entry
Database: PDB / ID: 7b41
TitleCrystal structure of c-MET bound by compound 7
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE / c-met / kinase / folded P-loop / 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 / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET Receptor Activation / MET interacts with TNS proteins / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling ...negative regulation of guanyl-nucleotide exchange factor activity / hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET Receptor Activation / MET interacts with TNS proteins / 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 / positive regulation of endothelial cell chemotaxis / negative regulation of stress fiber assembly / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of Rho protein signal transduction / 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 / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / cell surface receptor protein tyrosine kinase signaling pathway / basal plasma membrane / molecular function activator activity / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / liver development / Negative regulation of MET activity / receptor protein-tyrosine kinase / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / cell surface receptor signaling pathway / receptor complex / postsynapse / 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 / IPT domain / PSI domain / domain found in Plexins, Semaphorins and Integrins / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Immunoglobulin E-set / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-SWK / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.97 Å
AuthorsCollie, G.W.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Structural Basis for Targeting the Folded P-Loop Conformation of c-MET.
Authors: Collie, G.W. / Michaelides, I.N. / Embrey, K. / Stubbs, C.J. / Borjesson, U. / Dale, I.L. / Snijder, A. / Barlind, L. / Song, K. / Khurana, P. / Phillips, C. / Storer, R.I.
History
DepositionDec 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.title / _citation.year
Revision 1.2Feb 3, 2021Group: 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 / _citation.year
Revision 1.3May 1, 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)34,1622
Polymers33,7861
Non-polymers3751
Water2,486138
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.670, 42.620, 86.440
Angle α, β, γ (deg.)90.000, 122.070, 90.000
Int Tables number5
Space group name H-MC121

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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: 33786.207 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-SWK / 3-[(2-fluorophenyl)methyl]-5-(1-piperidin-4-ylpyrazol-4-yl)-1~{H}-pyrrolo[2,3-b]pyridine


Mass: 375.442 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22FN5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 138 / 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: 2.58 Å3/Da / Density % sol: 52.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 25 % PEG3350, 0.2 M MgCl2, 0.1 M bis-tris pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99987 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Aug 31, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 1.965→47.315 Å / Num. obs: 23793 / % possible obs: 95.6 % / Redundancy: 5 % / Biso Wilson estimate: 35.54 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.07 / Rrim(I) all: 0.157 / Net I/σ(I): 7.7 / Num. measured all: 119240
Reflection shellResolution: 1.965→1.999 Å / Redundancy: 4.7 % / Rmerge(I) obs: 1.632 / Num. unique obs: 1178 / CC1/2: 0.403 / Rpim(I) all: 0.838 / % possible all: 96.3

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Processing

Software
NameVersionClassification
Aimlessdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 1.97→47.31 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.934 / SU R Cruickshank DPI: 0.16 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.163 / SU Rfree Blow DPI: 0.148 / SU Rfree Cruickshank DPI: 0.147
RfactorNum. reflection% reflectionSelection details
Rfree0.233 1172 4.95 %RANDOM
Rwork0.196 ---
obs0.198 23671 95.1 %-
Displacement parametersBiso max: 111.61 Å2 / Biso mean: 42.06 Å2 / Biso min: 18.84 Å2
Baniso -1Baniso -2Baniso -3
1--7.3973 Å20 Å2-2.612 Å2
2--6.6971 Å20 Å2
3---0.7002 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 1.97→47.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2199 0 28 138 2365
Biso mean--39.5 46.15 -
Num. residues----281
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d770SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes374HARMONIC5
X-RAY DIFFRACTIONt_it2290HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion290SEMIHARMONIC5
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_contact2799SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2290HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3111HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion17.17
LS refinement shellResolution: 1.97→1.98 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2298 31 6.54 %
Rwork0.2291 443 -
all0.2292 474 -
obs--93.8 %

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