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- PDB-7b3z: Crystal structure of c-MET bound by compound 5 -

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Basic information

Entry
Database: PDB / ID: 7b3z
TitleCrystal structure of c-MET bound by compound 5
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / c-met / kinase / folded P-loop / 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 / MET activates PTPN11 / pancreas development / MET activates RAP1 and RAC1 / MET activates PI3K/AKT signaling / negative regulation of Rho protein signal transduction / negative regulation of stress fiber assembly / semaphorin-plexin signaling pathway / MET activates PTK2 signaling / negative regulation of thrombin-activated receptor signaling pathway / branching morphogenesis of an epithelial tube / positive chemotaxis / establishment of skin barrier / MET activates RAS signaling / MECP2 regulates neuronal receptors and channels / phagocytosis / positive regulation of microtubule polymerization / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator activity / neuron differentiation / Negative regulation of MET activity / 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 phosphatase binding / protein tyrosine kinase activity / positive regulation of protein kinase B signaling / cell surface receptor signaling pathway / receptor complex / 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
Chem-SV8 / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 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 1, 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

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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)34,1933
Polymers33,7861
Non-polymers4072
Water2,594144
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint2 kcal/mol
Surface area13700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.880, 42.450, 85.600
Angle α, β, γ (deg.)90.000, 120.860, 90.000
Int Tables number5
Space group name H-MC121

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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: 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-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-SV8 / 3-[3-(phenylmethyl)-1~{H}-pyrrolo[2,3-b]pyridin-5-yl]-4,5-dihydro-1~{H}-pyrrolo[3,4-b]pyrrol-6-one


Mass: 328.367 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H16N4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 144 / 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: 2.54 Å3/Da / Density % sol: 51.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 20 % PEG10000, 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 PILATUS3 S 6M / Detector: PIXEL / Date: Jul 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.8→21.34 Å / Num. obs: 31317 / % possible obs: 98.7 % / Redundancy: 3 % / Biso Wilson estimate: 31.1 Å2 / CC1/2: 0.998 / Net I/σ(I): 10.9
Reflection shellResolution: 1.8→1.83 Å / Num. unique obs: 1480 / CC1/2: 0.548

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Processing

Software
NameVersionClassification
Aimlessdata scaling
BUSTER2.11.6refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 1.8→21.34 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.935 / SU R Cruickshank DPI: 0.114 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.115 / SU Rfree Blow DPI: 0.106 / SU Rfree Cruickshank DPI: 0.106
RfactorNum. reflection% reflectionSelection details
Rfree0.215 1469 4.69 %RANDOM
Rwork0.193 ---
obs0.194 31316 98.7 %-
Displacement parametersBiso max: 93.08 Å2 / Biso mean: 37.64 Å2 / Biso min: 18.28 Å2
Baniso -1Baniso -2Baniso -3
1--7.2312 Å20 Å2-7.1358 Å2
2--7.6211 Å20 Å2
3----0.3899 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: final / Resolution: 1.8→21.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2171 0 29 144 2344
Biso mean--38.85 45.12 -
Num. residues----277
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d761SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes42HARMONIC2
X-RAY DIFFRACTIONt_gen_planes331HARMONIC5
X-RAY DIFFRACTIONt_it2271HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion288SEMIHARMONIC5
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_contact2749SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2271HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3086HARMONIC20.94
X-RAY DIFFRACTIONt_omega_torsion2.8
X-RAY DIFFRACTIONt_other_torsion16.8
LS refinement shellResolution: 1.8→1.86 Å / Rfactor Rfree error: 0 / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.217 115 4.16 %
Rwork0.207 2651 -
all0.207 2766 -
obs--95.32 %

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