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- PDB-3qti: c-Met Kinase in Complex with NVP-BVU972 -

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Basic information

Entry
Database: PDB / ID: 3qti
Titlec-Met Kinase in Complex with NVP-BVU972
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / TRANSERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / semaphorin receptor activity / positive regulation of endothelial cell chemotaxis ...hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / semaphorin receptor activity / positive regulation of endothelial cell chemotaxis / 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 / negative regulation of Rho protein signal transduction / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of thrombin-activated receptor signaling pathway / semaphorin-plexin signaling pathway / establishment of skin barrier / MET activates RAS signaling / phagocytosis / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / basal plasma membrane / negative regulation of autophagy / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator activity / Negative regulation of MET activity / receptor protein-tyrosine kinase / neuron differentiation / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / nervous system development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / cell surface receptor signaling pathway / receptor complex / phosphorylation / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-3QT / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsAppleton, B.A.
CitationJournal: Cancer Res. / Year: 2011
Title: A Drug Resistance Screen Using a Selective MET Inhibitor Reveals a Spectrum of Mutations That Partially Overlap with Activating Mutations Found in Cancer Patients.
Authors: Tiedt, R. / Degenkolbe, E. / Furet, P. / Appleton, B.A. / Wagner, S. / Schoepfer, J. / Buck, E. / Ruddy, D.A. / Monahan, J.E. / Jones, M.D. / Blank, J. / Haasen, D. / Drueckes, P. / ...Authors: Tiedt, R. / Degenkolbe, E. / Furet, P. / Appleton, B.A. / Wagner, S. / Schoepfer, J. / Buck, E. / Ruddy, D.A. / Monahan, J.E. / Jones, M.D. / Blank, J. / Haasen, D. / Drueckes, P. / Wartmann, M. / McCarthy, C. / Sellers, W.R. / Hofmann, F.
History
DepositionFeb 22, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 17, 2011Group: Database references
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hepatocyte growth factor receptor
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,6527
Polymers70,8082
Non-polymers8445
Water7,116395
1
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7803
Polymers35,4041
Non-polymers3762
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8724
Polymers35,4041
Non-polymers4683
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.690, 47.100, 81.200
Angle α, β, γ (deg.)103.94, 102.58, 90.04
Int Tables number1
Space group name H-MP1
Detailsmonomer

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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: 35404.016 Da / Num. of mol.: 2 / Fragment: kinase domain, residues 1050-1360
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-3QT / 6-{[6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]methyl}quinoline


Mass: 340.381 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H16N6
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 395 / 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: 2.18 Å3/Da / Density % sol: 43.6 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Equal Volumes Protein and a Reservoir Solution composed of 100 mM Hepes pH 7.5, 16% PEG 4000, 8% isopropanol, and 3 mM TCEP were mixed with microseeds., VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 2, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→44.339 Å / Num. all: 38882 / Num. obs: 38882 / % possible obs: 96.5 % / Redundancy: 3.9 % / Biso Wilson estimate: 20.19 Å2 / Rsym value: 0.109 / Net I/σ(I): 9.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRsym valueDiffraction-ID% possible all
2-2.113.90.4321.80.432195.9
2.11-2.243.90.3062.50.306195.8
2.24-2.393.90.2273.40.227196.6
2.39-2.593.90.1864.20.186197
2.59-2.833.90.1415.50.141196.8
2.83-3.173.90.0948.10.094197.3
3.17-3.663.80.0612.50.06196.7
3.66-4.483.70.04714.20.047195.8
4.48-6.333.70.04215.40.042196.7
6.33-44.3393.80.036150.036196.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASERphasing
BUSTER-TNTBUSTER 2.9.7refinement
PDB_EXTRACT3.1data extraction
XDSdata reduction
BUSTER2.9.7refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→39.39 Å / Cor.coef. Fo:Fc: 0.9272 / Cor.coef. Fo:Fc free: 0.9104 / Occupancy max: 1 / Occupancy min: 0.28 / SU R Cruickshank DPI: 0.19 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2135 1964 5.05 %RANDOM
Rwork0.1826 ---
obs0.1841 38877 96.1 %-
Displacement parametersBiso mean: 24.86 Å2
Baniso -1Baniso -2Baniso -3
1--1.4138 Å20.7535 Å20.1641 Å2
2--1.0789 Å2-1.3766 Å2
3---0.3349 Å2
Refine analyzeLuzzati coordinate error obs: 0.217 Å
Refinement stepCycle: LAST / Resolution: 2→39.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4539 0 60 395 4994
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014726HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.996406HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1586SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes90HARMONIC2
X-RAY DIFFRACTIONt_gen_planes678HARMONIC5
X-RAY DIFFRACTIONt_it4726HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.61
X-RAY DIFFRACTIONt_other_torsion15.8
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion5965
X-RAY DIFFRACTIONt_sum_occupancies11
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact57144
LS refinement shellResolution: 2→2.06 Å / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.2341 159 5.5 %
Rwork0.197 2731 -
all0.199 2890 -
obs--96.1 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.2993-0.42290.1653.0153-0.90193.6490.04770.40460.1808-0.4583-0.0740.0222-0.3128-0.06120.0263-0.05220.0684-0.0198-0.0730.0374-0.1217.552225.0563-27.492
20.6677-0.01280.16870.5604-0.02590.6590.04520.06270.0176-0.013-0.0161-0.0328-0.05180.0333-0.0291-0.08490.01350.0066-0.0376-0.00510.005821.808411.7597-6.7813
31.5521-0.2371-0.03741.65-0.34173.0581-0.0446-0.2547-0.14130.36610.03880.01720.3237-0.10730.0057-0.0245-0.0330.0128-0.05110.0248-0.08729.08527.782632.1748
40.66160.0193-0.11820.5287-0.06150.65560.0567-0.0783-0.02440.0308-0.0116-0.00670.06090.0384-0.0451-0.07980.0028-0.0093-0.0256-0.01150.010743.033840.138212.5619
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|1052 - A|1160 }A1052 - 1160
2X-RAY DIFFRACTION2{ A|1161 - A|1360 }A1161 - 1360
3X-RAY DIFFRACTION3{ B|1058 - B|1160 }B1058 - 1160
4X-RAY DIFFRACTION4{ B|1161 - B|1360 }B1161 - 1360

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