[English] 日本語
Yorodumi
- PDB-4r1v: Identification and optimization of pyridazinones as potent and se... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4r1v
TitleIdentification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PROTEIN KINASE / Transferase / 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 / negative regulation of autophagy / basal plasma membrane / 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-3E8 / GAMMA-BUTYROLACTONE / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.2 Å
AuthorsBlaukat, A. / Bladt, F. / Friese-Hamim, M. / Knuehl, C. / Fittschen, C. / Graedler, U. / Meyring, M. / Dorsch, D. / Stieber, F. / Schadt, O.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors.
Authors: Dorsch, D. / Schadt, O. / Stieber, F. / Meyring, M. / Gradler, U. / Bladt, F. / Friese-Hamim, M. / Knuhl, C. / Pehl, U. / Blaukat, A.
History
DepositionAug 7, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2015Group: Database references
Revision 1.2Feb 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7425
Polymers32,9911
Non-polymers7514
Water6,287349
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.000, 43.038, 84.844
Angle α, β, γ (deg.)90.00, 92.23, 90.00
Int Tables number4
Space group name H-MP1211

-
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: 32991.375 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP residues 1055-1345
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-3E8 / 3-[1-(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile


Mass: 492.572 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H28N6O2
#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.: 349 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.12 Å3/Da / Density % sol: 41.95 % / Description: NONE
Crystal growTemperature: 298 K / pH: 6.5
Details: PEG 8000, pH 6.5, VAPOR DIFFUSION, temperature 298K

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.9999
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: May 24, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.2→84.82 Å / Num. obs: 85595 / % possible obs: 97.3 % / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Rmerge(I) obs: 0.038
Reflection shellResolution: 1.2→1.23 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.41 / % possible all: 72.3

-
Processing

Software
NameVersionClassification
XDSdata scaling
PHASESphasing
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementResolution: 1.2→84.82 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.97 / SU B: 1.382 / SU ML: 0.027 / Cross valid method: THROUGHOUT / ESU R: 0.039 / ESU R Free: 0.039 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.176 1654 2 %RANDOM
Rwork0.146 ---
obs0.146 81815 97.5 %-
all-85595 --
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: 14.37 Å2
Baniso -1Baniso -2Baniso -3
1--0.12 Å20 Å2-0.08 Å2
2--0.11 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.2→84.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2305 0 55 349 2709
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222490
X-RAY DIFFRACTIONr_bond_other_d0.0010.022284
X-RAY DIFFRACTIONr_angle_refined_deg1.3931.9863379
X-RAY DIFFRACTIONr_angle_other_deg0.81935325
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6425303
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.38623.333102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.06115431
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5171514
X-RAY DIFFRACTIONr_chiral_restr0.0880.2370
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022734
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02513
X-RAY DIFFRACTIONr_nbd_refined0.2210.2523
X-RAY DIFFRACTIONr_nbd_other0.1730.22324
X-RAY DIFFRACTIONr_nbtor_refined0.1840.21240
X-RAY DIFFRACTIONr_nbtor_other0.0840.21337
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.2206
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2020.211
X-RAY DIFFRACTIONr_symmetry_vdw_other0.290.288
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1880.243
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.21421937
X-RAY DIFFRACTIONr_mcbond_other1.5652605
X-RAY DIFFRACTIONr_mcangle_it3.78932444
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.69341174
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.6016935
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr2.38535811
X-RAY DIFFRACTIONr_sphericity_free12.0393349
X-RAY DIFFRACTIONr_sphericity_bonded5.49734705
LS refinement shellResolution: 1.2→1.23 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.283 89 -
Rwork0.261 4661 -
obs--75.25 %

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more