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- PDB-3ccn: X-ray structure of c-Met with triazolopyridazine inhibitor. -

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Basic information

Entry
Database: PDB / ID: 3ccn
TitleX-ray structure of c-Met with triazolopyridazine inhibitor.
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / c-Met Kinase Triazolopyridazine / ATP-binding / Glycoprotein / Membrane / Nucleotide-binding / Phosphoprotein / Proto-oncogene / Receptor / Transmembrane / Tyrosine-protein kinase
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-LKG / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsAbrecht, B.K. / Harmange, J.-C. / Bauer, D. / Dussault, I. / long, A. / Bellon, S.F.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Discovery and Optimization of Triazolopyridazines as Potent and Selective Inhibitors of the c-Met Kinase.
Authors: Albrecht, B.K. / Harmange, J.C. / Bauer, D. / Berry, L. / Bode, C. / Boezio, A.A. / Chen, A. / Choquette, D. / Dussault, I. / Fridrich, C. / Hirai, S. / Hoffman, D. / Larrow, J.F. / Kaplan- ...Authors: Albrecht, B.K. / Harmange, J.C. / Bauer, D. / Berry, L. / Bode, C. / Boezio, A.A. / Chen, A. / Choquette, D. / Dussault, I. / Fridrich, C. / Hirai, S. / Hoffman, D. / Larrow, J.F. / Kaplan-Lefko, P. / Lin, J. / Lohman, J. / Long, A.M. / Moriguchi, J. / O'Connor, A. / Potashman, M.H. / Reese, M. / Rex, K. / Siegmund, A. / Shah, K. / Shimanovich, R. / Springer, S.K. / Teffera, Y. / Yang, Y. / Zhang, Y. / Bellon, S.F.
History
DepositionFeb 26, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6492
Polymers35,3471
Non-polymers3021
Water3,189177
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.058, 43.440, 157.827
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 / Scatter factor receptor / SF receptor / HGF/SF receptor / Met proto-oncogene ...HGF receptor / Scatter factor receptor / SF receptor / HGF/SF receptor / Met proto-oncogene tyrosine kinase / c-Met


Mass: 35346.910 Da / Num. of mol.: 1 / Fragment: protein kinase domain,c-Met kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-LKG / 4-[(6-phenyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]phenol


Mass: 302.330 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H14N4O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 177 / 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: 2.04 Å3/Da / Density % sol: 39.69 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.8
Details: 0.1M HEPES pH 7.8, 15% PEG 4K, 6% 2-Propanol, 40mM BME, and 3% Ethanol., VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 130 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Apr 4, 2006 / Details: varimax optics
RadiationMonochromator: none / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. all: 23768 / Num. obs: 21891 / % possible obs: 92.1 % / Observed criterion σ(F): -1 / Observed criterion σ(I): -1 / Redundancy: 3 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 28
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.17 / Mean I/σ(I) obs: 6.5 / Num. unique all: 1894 / % possible all: 81.9

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
CrystalCleardata collection
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2RFN
Resolution: 1.9→50 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.896 / SU B: 3.74 / SU ML: 0.114 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.213 / ESU R Free: 0.184 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27545 1089 5 %RANDOM
Rwork0.23603 ---
all0.2379 22451 --
obs0.2379 20714 92.26 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.952 Å2
Baniso -1Baniso -2Baniso -3
1-0.42 Å20 Å20 Å2
2--0.76 Å20 Å2
3----1.19 Å2
Refinement stepCycle: LAST / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2149 0 23 177 2349
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222229
X-RAY DIFFRACTIONr_angle_refined_deg1.0571.9713023
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8785270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.45623.33387
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.84115364
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.232159
X-RAY DIFFRACTIONr_chiral_restr0.0730.2340
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021654
X-RAY DIFFRACTIONr_nbd_refined0.1720.21013
X-RAY DIFFRACTIONr_nbtor_refined0.3020.21498
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1160.2144
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.160.236
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1020.211
X-RAY DIFFRACTIONr_mcbond_it0.6011.51417
X-RAY DIFFRACTIONr_mcangle_it0.99922204
X-RAY DIFFRACTIONr_scbond_it1.1443952
X-RAY DIFFRACTIONr_scangle_it1.6764.5819
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.368 71 -
Rwork0.308 1291 -
obs-1291 80.31 %

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