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- PDB-8vi1: Crystal structure of c-Met-D1228N in complex with KIN-7615 -

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Basic information

Entry
Database: PDB / ID: 8vi1
TitleCrystal structure of c-Met-D1228N in complex with KIN-7615
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE / c-Met D1228N KIN-7615
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 / 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
Similarity search - Domain/homology
: / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.11 Å
AuthorsOuyang, X. / Kania, R. / Cox, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of KIN-8741, a Highly Selective Type IIb c-Met Kinase Inhibitor with Broad Mutation Coverage and Quality Drug-Like Properties for the Treatment of Cancer.
Authors: Ouyang, X.S. / Grandinetti, K.B. / Boren, M. / Chakravorty, S. / Chopade, S. / Jiang, P. / Kanouni, T. / Koudriakova, T. / Makwana, O. / Pack, S.K. / Perez, M. / Suriben, R. / Timple, N. / ...Authors: Ouyang, X.S. / Grandinetti, K.B. / Boren, M. / Chakravorty, S. / Chopade, S. / Jiang, P. / Kanouni, T. / Koudriakova, T. / Makwana, O. / Pack, S.K. / Perez, M. / Suriben, R. / Timple, N. / Thohan, S. / Uryu, S. / Womble, S. / Yuan, D. / Kania, R.S. / Cox, J.M.
History
DepositionJan 2, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)70,6784
Polymers69,6832
Non-polymers9952
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4230 Å2
ΔGint-17 kcal/mol
Surface area27850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.660, 69.820, 78.060
Angle α, β, γ (deg.)90.00, 95.84, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Hepatocyte growth factor receptor / 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: 34841.332 Da / Num. of mol.: 2
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-A1AB1 / N-(3,5-difluoro-4-{[6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide


Mass: 497.448 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H21F2N3O6 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: 2.87 Å3/Da / Density % sol: 57.08 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 0.1M HEPES pH7.5, 12.5% PEG4000, 10% isopropanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 14, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.11→43.83 Å / Num. obs: 11252 / % possible obs: 78.3 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.105 / Net I/σ(I): 11.7
Reflection shellResolution: 3.11→3.32 Å / Rmerge(I) obs: 0.372 / Num. unique obs: 384

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.11→43.83 Å / Cor.coef. Fo:Fc: 0.877 / Cor.coef. Fo:Fc free: 0.804 / SU B: 64.504 / SU ML: 0.488 / Cross valid method: THROUGHOUT / ESU R Free: 0.669 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29791 500 4.4 %RANDOM
Rwork0.25112 ---
obs0.2531 10751 78.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 72.851 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å2-0 Å20.26 Å2
2--0.02 Å2-0 Å2
3----0.33 Å2
Refinement stepCycle: 1 / Resolution: 3.11→43.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4545 0 72 0 4617
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0124732
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164418
X-RAY DIFFRACTIONr_angle_refined_deg0.611.6546408
X-RAY DIFFRACTIONr_angle_other_deg0.231.56510276
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.3355565
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.5091026
X-RAY DIFFRACTIONr_dihedral_angle_3_deg9.96510819
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0290.2711
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.025241
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02943
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3443.8592278
X-RAY DIFFRACTIONr_mcbond_other0.3443.8592278
X-RAY DIFFRACTIONr_mcangle_it0.6495.7832837
X-RAY DIFFRACTIONr_mcangle_other0.6495.7852838
X-RAY DIFFRACTIONr_scbond_it0.1633.8672454
X-RAY DIFFRACTIONr_scbond_other0.1633.8672455
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.3495.8083572
X-RAY DIFFRACTIONr_long_range_B_refined2.31449.5465360
X-RAY DIFFRACTIONr_long_range_B_other2.31349.5425361
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.11→3.19 Å
RfactorNum. reflection% reflection
Rfree0.361 4 -
Rwork0.282 74 -
obs--7.31 %
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)
10.9436-2.19280.1478.0594-3.27722.96810.12590.0631-0.0046-0.2517-0.107-0.0423-0.0898-0.0566-0.01890.3851-0.113-0.01150.487-0.02580.30428.641614.979327.1084
24.28511.13782.86159.14663.97854.76920.05530.2735-0.0365-0.15540.1597-0.23840.10550.5191-0.2150.1873-0.0590.06480.35520.04550.186817.7583-3.594116.0126
33.11790.7444-2.88384.57250.69784.11470.60680.23250.78070.2004-0.2802-0.6653-1.1773-0.0145-0.32660.6546-0.2839-0.15450.63140.09750.936210.96362.066725.1511
43.90241.4393-1.42714.60290.25584.73080.11280.1186-0.15670.0207-0.2093-0.95610.28810.50210.09650.221-0.0463-0.00540.23290.07660.22234.6983-14.879727.3634
55.1691-7.13034.07649.9053-5.61363.2455-0.6346-0.09380.30440.88670.3318-0.328-0.6178-0.01540.30280.5887-0.2033-0.05650.73350.0950.5078-3.3755-1.518416.8843
67.0294-5.57330.9166.3147-0.68465.88890.1167-0.1233-0.3786-0.1614-0.00870.432-0.1240.0587-0.1080.0298-0.03370.01030.0605-0.03190.0481-10.3065-12.969821.9167
73.7653-0.42031.51144.1529-0.27226.14160.0865-0.1316-0.61780.1220.07530.57920.5222-0.0942-0.16170.1408-0.08370.05490.1132-0.0030.189-11.5516-22.35626.2291
80.8968-2.698-0.896212.2090.40662.30380.2349-0.09790.1507-0.7612-0.1298-0.2531-0.09690.5583-0.10510.422-0.04530.02970.7240.11530.5103-16.344937.6619-1.4561
91.5401-3.31840.68289.47280.04245.4598-0.1938-0.0131-0.17760.4998-0.11840.6523-0.5512-0.02350.31220.2835-0.2025-0.01860.2697-0.06230.4425-17.348229.161213.4605
101.16890.49470.4767.5064-2.19292.46930.0951-0.18140.13720.09690.18180.6556-0.29-0.0486-0.27690.0738-0.02550.05790.2449-0.03130.422-26.209819.77289.0014
110.607-0.42841.71663.81920.10176.78130.2140.19770.1154-1.10770.12390.3299-0.03110.3689-0.33780.3950.02410.08780.29260.1410.6009-21.543811.58612.5775
125.3467-2.10160.45146.0354-0.43873.75810.14860.0993-0.1035-0.8187-0.02461.12380.4569-0.3496-0.1240.2876-0.1437-0.18240.12350.02690.3173-26.3489-2.80865.7036
136.55225.4147-4.166210.2577-9.33078.6478-0.008-0.05910.10830.08380.10230.1034-0.096-0.146-0.09430.1567-0.0119-0.07340.31310.00410.3727-41.31943.47519.0189
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1053 - 1072
2X-RAY DIFFRACTION2A1073 - 1091
3X-RAY DIFFRACTION3A1092 - 1152
4X-RAY DIFFRACTION4A1153 - 1217
5X-RAY DIFFRACTION5A1218 - 1238
6X-RAY DIFFRACTION6A1243 - 1278
7X-RAY DIFFRACTION7A1279 - 1346
8X-RAY DIFFRACTION8B1050 - 1075
9X-RAY DIFFRACTION9B1076 - 1117
10X-RAY DIFFRACTION10B1118 - 1197
11X-RAY DIFFRACTION11B1198 - 1261
12X-RAY DIFFRACTION12B1262 - 1329
13X-RAY DIFFRACTION13B1330 - 1345

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