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- PDB-5hlw: Crystal structure of c-Met mutant Y1230H in complex with compound 14 -

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Basic information

Entry
Database: PDB / ID: 5hlw
TitleCrystal structure of c-Met mutant Y1230H in complex with compound 14
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / TRANSFERASE 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-62E / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.97 Å
AuthorsVallee, F. / Pouzieux, S. / Marquette, J.P. / Houtmann, J.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol- ...Title: Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844).
Authors: Ugolini, A. / Kenigsberg, M. / Rak, A. / Vallee, F. / Houtmann, J. / Lowinski, M. / Capdevila, C. / Khider, J. / Albert, E. / Martinet, N. / Nemecek, C. / Grapinet, S. / Bacque, E. / ...Authors: Ugolini, A. / Kenigsberg, M. / Rak, A. / Vallee, F. / Houtmann, J. / Lowinski, M. / Capdevila, C. / Khider, J. / Albert, E. / Martinet, N. / Nemecek, C. / Grapinet, S. / Bacque, E. / Roesner, M. / Delaisi, C. / Calvet, L. / Bonche, F. / Semiond, D. / Egile, C. / Goulaouic, H. / Schio, L.
History
DepositionJan 15, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Nov 23, 2016Provider: repository / Type: Initial release

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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)34,4763
Polymers33,8761
Non-polymers6002
Water3,459192
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-13 kcal/mol
Surface area14340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.320, 46.690, 156.960
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 33876.277 Da / Num. of mol.: 1 / Mutation: Y1230H
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-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-62E / 1-[2-(1-ethylpiperidin-4-yl)ethyl]-3-(6-{[6-(thiophen-2-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)urea


Mass: 564.749 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H28N8OS3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 192 / 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: 2.48 Å3/Da / Density % sol: 50.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: Tris 100mM-MPD20%-pH8 / PH range: 8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 4, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 1.97→34.84 Å / Num. obs: 21753 / % possible obs: 100 % / Redundancy: 4 % / Net I/σ(I): 8.8
Reflection shellResolution: 1.97→2.02 Å / Redundancy: 3 % / Rmerge(I) obs: 0.235 / Mean I/σ(I) obs: 3.4 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementResolution: 1.97→34.84 Å / Cor.coef. Fo:Fc: 0.9348 / Cor.coef. Fo:Fc free: 0.9261 / SU R Cruickshank DPI: 0.161 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.172 / SU Rfree Blow DPI: 0.144 / SU Rfree Cruickshank DPI: 0.14
Num. reflection% reflectionSelection details
Rfree1175 5.12 %RANDOM
obs22929 98.3 %-
Displacement parametersBiso mean: 38.36 Å2
Baniso -1Baniso -2Baniso -3
1--2.3266 Å20 Å20 Å2
2--4.9032 Å20 Å2
3----2.5766 Å2
Refine analyzeLuzzati coordinate error obs: 0.201 Å
Refinement stepCycle: LAST / Resolution: 1.97→34.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2250 0 39 192 2481
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012345HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.013173HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d796SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes44HARMONIC2
X-RAY DIFFRACTIONt_gen_planes370HARMONIC5
X-RAY DIFFRACTIONt_it2345HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.73
X-RAY DIFFRACTIONt_other_torsion17.48
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion295SEMIHARMONIC5
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_contact2859SEMIHARMONIC4
LS refinement shellResolution: 1.97→2.06 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2538 158 5.66 %
Rwork0.1996 2635 -
all0.2025 2793 -
obs--98.3 %

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