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- PDB-4knb: C-Met in complex with OSI ligand -

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Basic information

Entry
Database: PDB / ID: 4knb
TitleC-Met in complex with OSI ligand
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / protein kinase
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-1RU / GAMMA-BUTYROLACTONE / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.4 Å
AuthorsWang, J. / Steinig, A.G. / Li, A.H. / Chen, X. / Dong, H. / Ferraro, C. / Jin, M. / Kadalbajoo, M. / Kleinberg, A. / Stolz, K.M. ...Wang, J. / Steinig, A.G. / Li, A.H. / Chen, X. / Dong, H. / Ferraro, C. / Jin, M. / Kadalbajoo, M. / Kleinberg, A. / Stolz, K.M. / Tavares-Greco, P.A. / Wang, T. / Albertella, M.R. / Peng, Y. / Crew, L. / Kahler, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Novel 6-aminofuro[3,2-c]pyridines as potent, orally efficacious inhibitors of cMET and RON kinases.
Authors: Steinig, A.G. / Li, A.H. / Wang, J. / Chen, X. / Dong, H. / Ferraro, C. / Jin, M. / Kadalbajoo, M. / Kleinberg, A. / Stolz, K.M. / Tavares-Greco, P.A. / Wang, T. / Albertella, M.R. / Peng, Y. ...Authors: Steinig, A.G. / Li, A.H. / Wang, J. / Chen, X. / Dong, H. / Ferraro, C. / Jin, M. / Kadalbajoo, M. / Kleinberg, A. / Stolz, K.M. / Tavares-Greco, P.A. / Wang, T. / Albertella, M.R. / Peng, Y. / Crew, L. / Kahler, J. / Kan, J. / Schulz, R. / Cooke, A. / Bittner, M. / Turton, R.W. / Franklin, M. / Gokhale, P. / Landfair, D. / Mantis, C. / Workman, J. / Wild, R. / Pachter, J. / Epstein, D. / Mulvihill, M.J.
History
DepositionMay 9, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 30, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
C: Hepatocyte growth factor receptor
D: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,41911
Polymers130,1994
Non-polymers2,2207
Water1,40578
1
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2124
Polymers32,5501
Non-polymers6633
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1263
Polymers32,5501
Non-polymers5762
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0402
Polymers32,5501
Non-polymers4901
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0402
Polymers32,5501
Non-polymers4901
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.713, 85.922, 156.469
Angle α, β, γ (deg.)90.00, 91.47, 90.00
Int Tables number4
Space group name H-MP1211

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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: 32549.855 Da / Num. of mol.: 4 / Fragment: protein kinase domain (UNP residues 1060-1346)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Insecta (true insects)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-1RU / 7-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]furo[3,2-c]pyridin-6-amine


Mass: 490.357 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H22Cl2FN5O2
#3: Chemical ChemComp-GBL / GAMMA-BUTYROLACTONE / DIHYDROFURAN-2(3H)-ONE / Gamma-Butyrolactone


Mass: 86.089 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 78 / 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: 2.31 Å3/Da / Density % sol: 46.7 %
Crystal growMethod: liquid diffusion / Details: LIQUID DIFFUSION

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.9999
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.4→24.95 Å / Num. obs: 46168 / % possible obs: 99.3 % / Observed criterion σ(I): 0 / Redundancy: 4.1 % / Rmerge(I) obs: 0.053
Reflection shellResolution: 2.4→2.46 Å / Redundancy: 4 % / Rmerge(I) obs: 0.647 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementResolution: 2.4→24.95 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.911 / SU B: 27.101 / SU ML: 0.299 / Cross valid method: THROUGHOUT / ESU R: 0.511 / ESU R Free: 0.303 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28778 1062 2.3 %RANDOM
Rwork0.23966 ---
obs0.2408 45105 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 84.381 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å20 Å2-3.47 Å2
2---0.28 Å20 Å2
3---0.08 Å2
Refinement stepCycle: LAST / Resolution: 2.4→24.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8355 0 150 78 8583
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0228671
X-RAY DIFFRACTIONr_bond_other_d0.0020.028018
X-RAY DIFFRACTIONr_angle_refined_deg0.9171.9811738
X-RAY DIFFRACTIONr_angle_other_deg0.709318574
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.12551034
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.00822.765340
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.504151465
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5611547
X-RAY DIFFRACTIONr_chiral_restr0.0510.21307
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.029349
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021810
X-RAY DIFFRACTIONr_nbd_refined0.1720.21756
X-RAY DIFFRACTIONr_nbd_other0.1630.27814
X-RAY DIFFRACTIONr_nbtor_refined0.1720.24182
X-RAY DIFFRACTIONr_nbtor_other0.080.24408
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1320.2180
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1140.230
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1670.290
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1540.29
X-RAY DIFFRACTIONr_mcbond_it1.26426761
X-RAY DIFFRACTIONr_mcbond_other0.20822133
X-RAY DIFFRACTIONr_mcangle_it1.58838463
X-RAY DIFFRACTIONr_scbond_it2.21444149
X-RAY DIFFRACTIONr_scangle_it2.96563275
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.396 77 -
Rwork0.322 3285 -
obs--100 %
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)
18.48711.0015.22773.54650.71267.6981-0.08621.43490.0166-0.75250.04930.12910.1392-0.18050.0370.0311-0.0542-0.01570.0921-0.07860.05867.936-10.83111.489
22.82520.67440.33654.99780.42573.09860.0480.09980.043-0.23550.14130.1954-0.0437-0.1524-0.1893-0.28910.03720.0643-0.325-0.0337-0.356621.3464.76828.415
316.062.07668.21227.15782.729616.64390.4216-3.20260.43261.8422-0.3236-1.3885-0.4165-0.3705-0.0980.5836-0.1322-0.27070.4728-0.01580.22497.20917.04866.62
43.3345-0.83151.85755.8527-1.13953.3775-0.2706-0.32050.31540.69550.0383-0.4161-0.34860.01040.2323-0.1360.00960.0515-0.2348-0.0974-0.3004-5.48528.548.794
515.25371.16469.67017.30252.62515.15530.0653-2.84680.72561.06010.0485-0.6112-0.2327-0.262-0.11380.11370.04730.07490.47080.13730.166711.95-27.10469.1
64.9827-1.60551.91394.4251-1.25864.3828-0.0686-0.3375-0.13850.11090.0036-0.2181-0.14-0.01470.0649-0.28580.01740.0782-0.19930.0135-0.3174-2.984-14.63851.012
712.8327-1.41654.36534.6977-0.42988.29820.25112.5830.2639-1.5439-0.27080.4946-0.01710.13930.01960.2975-0.0372-0.10740.3574-0.00230.018612.14134.4524.144
84.810.08991.47244.26940.23983.8255-0.14930.11571.0883-0.2748-0.00360.1717-0.6826-0.54890.1529-0.0110.08820.044-0.1514-0.07970.058123.05848.26423.952
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1064 - 1159
2X-RAY DIFFRACTION2A1160 - 1344
3X-RAY DIFFRACTION3B1067 - 1159
4X-RAY DIFFRACTION4B1160 - 1346
5X-RAY DIFFRACTION5C1060 - 1159
6X-RAY DIFFRACTION6C1160 - 1346
7X-RAY DIFFRACTION7D1064 - 1159
8X-RAY DIFFRACTION8D1160 - 1346

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