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- PDB-7v3s: Crystal structure of CMET in complex with a novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 7v3s
TitleCrystal structure of CMET in complex with a novel inhibitor
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE/INHIBITOR / 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 / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling ...hepatocyte growth factor receptor activity / 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 interacts with TNS proteins / MET Receptor Activation / 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 / 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 / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / phagocytosis / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / liver development / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / molecular function activator activity / receptor protein-tyrosine kinase / Negative regulation of MET activity / neuron differentiation / 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 tyrosine kinase activity / protein phosphatase binding / postsynapse / receptor complex / cell surface receptor signaling pathway / 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 / PSI domain / domain found in Plexins, Semaphorins and Integrins / IPT domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin E-set / Tyrosine-protein kinase, active site / 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
Chem-5I9 / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsSu, H.X. / Liu, Q.F. / Chen, T.T. / Li, M.J. / Xu, Y.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of 10H-Benzo[b]pyrido[2,3-e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c-Met Kinase
Authors: Zhan, Z. / Ji, Y. / Su, H. / Fang, C. / Peng, X. / Liu, Q. / Dai, Y. / Lin, D. / Xu, Y. / Ai, J. / Duan, W.
History
DepositionAug 11, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 17, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2023Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)36,5482
Polymers36,0341
Non-polymers5141
Water5,062281
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13390 Å2
Unit cell
Length a, b, c (Å)42.999, 80.397, 91.047
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 36033.594 Da / Num. of mol.: 1 / Fragment: UNP residues 1038-1346
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5I9 / ~{N}1'-[3-fluoranyl-4-(10~{H}-pyrido[3,2-b][1,4]benzoxazin-4-yloxy)phenyl]-~{N}1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


Mass: 514.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H20F2N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 281 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 43.67 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M HEPES, 8% isopropanol, 3mM TECP, 16% PEG4000, pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9785 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 10, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 25616 / % possible obs: 99.9 % / Redundancy: 7 % / Rmerge(I) obs: 0.1 / Χ2: 0.986 / Net I/σ(I): 7.7 / Num. measured all: 179020
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.9-1.937.10.49112370.944199.8
1.93-1.9770.44512410.923199.9
1.97-2.017.10.39412500.951199.9
2.01-2.057.10.32312690.977199.8
2.05-2.097.10.27712501.031199.8
2.09-2.147.10.24712721.034199.9
2.14-2.197.10.22112561.0151100
2.19-2.257.10.18712721.0361100
2.25-2.327.10.17412541.0211100
2.32-2.397.10.15112980.988199.9
2.39-2.487.20.13412460.9471100
2.48-2.587.10.12112800.943199.9
2.58-2.77.20.10312780.9061100
2.7-2.847.20.09412680.9061100
2.84-3.027.10.08412880.963199.9
3.02-3.256.90.08112931.1121100
3.25-3.586.70.0713101.2021100
3.58-4.096.60.06612881.2181100
4.09-5.166.60.0513400.7841100
5.16-506.60.05514260.838199.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation5.89 Å45.52 Å

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHASER2.8.3phasing
PHENIX1.17.1-3660refinement
PDB_EXTRACT3.27data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GG5

4gg5


Resolution: 1.9→36.77 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 17.21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1954 1213 4.8 %
Rwork0.164 24078 -
obs0.1655 25291 98.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 61.05 Å2 / Biso mean: 23.4174 Å2 / Biso min: 6.12 Å2
Refinement stepCycle: final / Resolution: 1.9→36.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2203 0 38 281 2522
Biso mean--16.1 33.17 -
Num. residues----284
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.9-1.970.24581270.19812394252191
1.97-2.060.20161330.17612608274198
2.06-2.170.19281270.16326742801100
2.17-2.310.1891230.158826772800100
2.31-2.490.19861500.160126692819100
2.49-2.740.20751390.166327022841100
2.74-3.130.18831220.160127332855100
3.13-3.950.18161570.155227362893100
3.95-36.770.19511350.166828853020100
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)
13.5185-0.32460.37845.0158-0.13932.98-0.0439-0.29010.13960.2643-0.0026-0.371-0.12860.35760.03540.07610.0097-0.00950.1612-0.01740.08882.5738-13.844513.6002
25.1991.35690.06492.76230.37431.40350.0191-0.04840.00050.0538-0.0091-0.1088-0.0390.0791-0.01910.07230.01340.00610.08670.01580.0265-0.5509-17.16024.8382
31.45040.1915-0.14343.32321.35753.4271-0.012-0.19850.11780.3793-0.0317-0.0195-0.0787-0.03730.03650.14760.0270.01070.1582-0.0210.1277-14.2071-11.166937.5308
42.1234-0.2968-1.10181.99910.70514.1343-0.0174-0.23060.00570.2544-0.0165-0.18770.09350.16640.03110.09720.0234-0.02190.11250.00030.126-8.4057-19.498521.1927
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1247 through 1288 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 1289 through 1346 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 1053 through 1153 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 1154 through 1246 )A0

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