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- PDB-3c1x: Crystal structure of the tyrosine kinase domain of the hepatocyte... -

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Basic information

Entry
Database: PDB / ID: 3c1x
TitleCrystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-MET in complex with a Pyrrolotriazine based inhibitor
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE / RECEPTOR TYROSINE KINASE / SIGNAL TRANSDUCTION / GRB2 / SHC / ATP-binding / Glycoprotein / Membrane / Nucleotide-binding / Phosphoprotein / Proto-oncogene / Transmembrane / Tyrosine-protein kinase
Function / homology
Function and homology information


negative regulation of guanyl-nucleotide exchange factor 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 ...negative regulation of guanyl-nucleotide exchange factor 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 / negative regulation of stress fiber assembly / positive regulation of endothelial cell chemotaxis / 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 / liver development / molecular function activator activity / InlB-mediated entry of Listeria monocytogenes into host cell / basal plasma membrane / excitatory postsynaptic potential / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / Negative regulation of MET activity / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein phosphatase binding / receptor complex / cell surface receptor signaling pathway / 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-CKK / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 Å
AuthorsSack, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase.
Authors: Schroeder, G.M. / Chen, X.T. / Williams, D.K. / Nirschl, D.S. / Cai, Z.W. / Wei, D. / Tokarski, J.S. / An, Y. / Sack, J. / Chen, Z. / Huynh, T. / Vaccaro, W. / Poss, M. / Wautlet, B. / Gullo- ...Authors: Schroeder, G.M. / Chen, X.T. / Williams, D.K. / Nirschl, D.S. / Cai, Z.W. / Wei, D. / Tokarski, J.S. / An, Y. / Sack, J. / Chen, Z. / Huynh, T. / Vaccaro, W. / Poss, M. / Wautlet, B. / Gullo-Brown, J. / Kellar, K. / Manne, V. / Hunt, J.T. / Wong, T.W. / Lombardo, L.J. / Fargnoli, J. / Borzilleri, R.M.
History
DepositionJan 24, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)42,3852
Polymers41,8491
Non-polymers5361
Water1,65792
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.781, 46.153, 151.022
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 / MET PROTO-ONCOGENE TYROSINE KINASE / C-MET / HGF RECEPTOR / HGF/SF RECEPTOR / SF receptor / Scatter ...MET PROTO-ONCOGENE TYROSINE KINASE / C-MET / HGF RECEPTOR / HGF/SF RECEPTOR / SF receptor / Scatter factor receptor


Mass: 41849.277 Da / Num. of mol.: 1 / Fragment: tyrosine kinase domain, UNP residues 1049-1360 / Mutation: Y1194F, Y1234F, Y1235D, V1272L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Cell line (production host): SPODOPTERA FRUGIPERDA 9 (Sf9) / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-CKK / N-{[4-({5-[(4-aminopiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl}oxy)-3-fluorophenyl]carbamoyl}-2-(4-fluorophenyl)acetamide


Mass: 535.545 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H27F2N7O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / 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: 1.78 Å3/Da / Density % sol: 30.95 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC / Detector: CCD / Date: Oct 23, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.17→50 Å / Num. obs: 13241 / % possible obs: 78.1 % / Observed criterion σ(I): 0 / Redundancy: 3 % / Biso Wilson estimate: 43.346 Å2 / Rmerge(I) obs: 0.108 / Net I/σ(I): 10.1
Reflection shellResolution: 2.17→2.37 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.361 / Mean I/σ(I) obs: 1.7 / % possible all: 65.5

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Processing

Software
NameVersionClassification
AMoREphasing
BUSTER-TNT2.1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.17→37.76 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2617 791 5.97 %RANDOM
Rwork0.2046 ---
obs0.2081 13241 80.48 %-
Displacement parametersBiso mean: 54.86 Å2
Baniso -1Baniso -2Baniso -3
1--2.98288137 Å20 Å20 Å2
2--4.35454477 Å20 Å2
3----1.3716634 Å2
Refinement stepCycle: LAST / Resolution: 2.17→37.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2309 0 39 92 2440
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.00424102
X-RAY DIFFRACTIONt_angle_deg0.7532552
X-RAY DIFFRACTIONt_dihedral_angle_d23.4064630
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes0.005612
X-RAY DIFFRACTIONt_gen_planes0.0093445
X-RAY DIFFRACTIONt_it1.009241020
X-RAY DIFFRACTIONt_nbd0.029755
LS refinement shellResolution: 2.17→2.31 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.3134 77 4.75 %
Rwork0.2524 1545 -
all0.2553 1622 -
obs--80.48 %

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