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- PDB-5hti: Crystal structure of c-Met kinase domain in complex with LXM108 -

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Basic information

Entry
Database: PDB / ID: 5hti
TitleCrystal structure of c-Met kinase domain in complex with LXM108
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / c-Met 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-66L / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.66 Å
AuthorsLiu, Q.F. / Xu, Y.C.
CitationJournal: to be published
Title: Crystal structure of c-Met kinase domain in complex with LXM108
Authors: Xu, Y.C. / Long, Y.
History
DepositionJan 26, 2016Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Feb 1, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector

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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)36,6232
Polymers36,0341
Non-polymers5901
Water3,873215
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13730 Å2
Unit cell
Length a, b, c (Å)42.894, 80.557, 91.449
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 36033.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-66L / N-[3-fluoro-4-({7-[2-(morpholin-4-yl)ethoxy]-1,6-naphthyridin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


Mass: 589.589 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H29F2N5O5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 215 / Source method: isolated from a natural source / Formula: H2O

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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: 2.19 Å3/Da / Density % sol: 43.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.1
Details: 10-11% PEG5000MME, 11% isopropanol, 0.1M HEPES pH 7.1

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9786 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 10, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
10.97911
20.97861
ReflectionResolution: 1.66→50 Å / Num. obs: 38131 / % possible obs: 99.7 % / Redundancy: 10.8 % / Biso Wilson estimate: 17.12 Å2 / Rmerge(I) obs: 0.072 / Net I/av σ(I): 38.262 / Net I/σ(I): 7.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
1.66-1.6910.80.307199.9
1.69-1.7210.80.284199.6
1.72-1.7510.70.247199.9
1.75-1.7910.70.229199.8
1.79-1.8310.80.1881100
1.83-1.8710.60.173199.8
1.87-1.9210.50.1561100
1.92-1.979.60.145199.2
1.97-2.0310.10.132199.8
2.03-2.0911.40.111199.9
2.09-2.1711.30.104199.8
2.17-2.2511.30.093199.8
2.25-2.3611.20.085199.9
2.36-2.4811.20.079199.9
2.48-2.6310.70.071100
2.63-2.849.50.068198.9
2.84-3.1211.30.0611100
3.12-3.5811.40.0561100
3.58-4.510.90.051199.9
4.5-5010.20.058198.4

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.51 Å31.28 Å
Translation6.51 Å31.28 Å

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Processing

Software
NameVersionClassification
HKL-3000data collection
HKL-3000data scaling
HKL-30002.5.5data processing
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MXC
Resolution: 1.66→31.283 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.44
RfactorNum. reflection% reflection
Rfree0.2056 2000 5.25 %
Rwork0.181 --
obs0.1823 38060 99.49 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 66.54 Å2 / Biso mean: 23.6161 Å2 / Biso min: 7.94 Å2
Refinement stepCycle: final / Resolution: 1.66→31.283 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2306 0 43 215 2564
Biso mean--19.48 27.97 -
Num. residues----290
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082423
X-RAY DIFFRACTIONf_angle_d1.4463289
X-RAY DIFFRACTIONf_chiral_restr0.261363
X-RAY DIFFRACTIONf_plane_restr0.005411
X-RAY DIFFRACTIONf_dihedral_angle_d13.211887
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6595-1.7010.2361360.19212436X-RAY DIFFRACTION96
1.701-1.7470.2391400.18572545X-RAY DIFFRACTION100
1.747-1.79840.22311420.18612552X-RAY DIFFRACTION100
1.7984-1.85640.20231410.18042548X-RAY DIFFRACTION100
1.8564-1.92270.24381410.17832546X-RAY DIFFRACTION100
1.9227-1.99970.22481410.18742551X-RAY DIFFRACTION99
1.9997-2.09070.19381430.18472557X-RAY DIFFRACTION100
2.0907-2.20090.20631420.18182568X-RAY DIFFRACTION100
2.2009-2.33870.23871430.17722587X-RAY DIFFRACTION100
2.3387-2.51920.18781430.17322581X-RAY DIFFRACTION100
2.5192-2.77260.20841440.18982591X-RAY DIFFRACTION100
2.7726-3.17350.23231460.19482611X-RAY DIFFRACTION100
3.1735-3.9970.19041450.17792643X-RAY DIFFRACTION100
3.997-4.50.18711530.16562744X-RAY DIFFRACTION99

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