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- PDB-2x2m: Crystal Structure of phosphorylated RET tyrosine kinase domain wi... -

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Basic information

Entry
Database: PDB / ID: 2x2m
TitleCrystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor
ComponentsPROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
KeywordsTRANSFERASE / HIRSCHSPRUNG DISEASE / GDNF RECEPTOR / TRANSMEMBRANE / PROTO-ONCOGENE / PHOSPHOPROTEIN / DISEASE MUTATION / PHOSPHOTRANSFERASE / RET / KINASE / MEMBRANE
Function / homology
Function and homology information


Peyer's patch morphogenesis / GDF15-GFRAL signaling pathway / positive regulation of metanephric glomerulus development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / posterior midgut development / Formation of the ureteric bud / membrane protein proteolysis ...Peyer's patch morphogenesis / GDF15-GFRAL signaling pathway / positive regulation of metanephric glomerulus development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / posterior midgut development / Formation of the ureteric bud / membrane protein proteolysis / Formation of the nephric duct / enteric nervous system development / neuron cell-cell adhesion / plasma membrane protein complex / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of cell adhesion mediated by integrin / neural crest cell migration / ureteric bud development / regulation of axonogenesis / response to pain / homophilic cell-cell adhesion / RET signaling / positive regulation of cell size / regulation of cell adhesion / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of neuron projection development / receptor protein-tyrosine kinase / MAPK cascade / signaling receptor activity / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / positive regulation of MAPK cascade / positive regulation of cell migration / axon / calcium ion binding / positive regulation of gene expression / positive regulation of DNA-templated transcription / signal transduction / ATP binding / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / : / RET Cadherin like domain 1 / RET Cadherin like domain 3 / RET Cadherin like domain 4 / RET, Cysteine Rich Domain / Cadherin domain ...Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / : / RET Cadherin like domain 1 / RET Cadherin like domain 3 / RET Cadherin like domain 4 / RET, Cysteine Rich Domain / Cadherin domain / Cadherin-like / Cadherins domain profile. / Cadherin-like superfamily / : / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / 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
FORMIC ACID / Chem-X2M / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsKnowles, P.P. / Murray-Rust, J. / Kjaer, S. / McDonald, N.Q.
CitationJournal: Bioorg. Med. Chem. / Year: 2010
Title: Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
Authors: Mologni, L. / Rostagno, R. / Brussolo, S. / Knowles, P.P. / Kjaer, S. / Murray-Rust, J. / Rosso, E. / Zambon, A. / Scapozza, L. / McDonald, N.Q. / Lucchini, V. / Gambacorti-Passerini, C.
History
DepositionJan 13, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 9, 2010Provider: repository / Type: Initial release
Revision 1.1Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.2Feb 28, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name
Revision 1.3Jan 30, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.4May 8, 2019Group: Data collection / Derived calculations / Experimental preparation
Category: exptl_crystal_grow / struct_conn
Item: _exptl_crystal_grow.temp / _struct_conn.pdbx_leaving_atom_flag
Revision 1.5Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
B: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2839
Polymers71,5762
Non-polymers7077
Water81145
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3700 Å2
ΔGint-20.1 kcal/mol
Surface area24030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.697, 50.760, 74.588
Angle α, β, γ (deg.)103.50, 99.66, 89.92
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-0.00142, -1, -0.00251), (-1, 0.00142, -0.00065), (0.00065, 0.00251, -1)
Vector: -8.12835, -8.14759, 33.33179)

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Components

#1: Protein PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET / RET TYROSINE KINASE RECEPTOR / C-RET


Mass: 35788.215 Da / Num. of mol.: 2 / Fragment: TYROSINE KINASE DOMAIN, RESIDUES 705-1013
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PBACPAK-HIS3 (CLONTECH) MODIFIED / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P07949, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: CH2O2
#3: Chemical ChemComp-X2M / (3Z)-3-[(3,5-DIMETHYL-1H-PYRROL-2-YL)METHYLIDENE]-1,3-DIHYDRO-2H-INDOL-2-ONE


Mass: 238.284 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H14N2O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence details705-1013 CORRESPOND WITH P07949, 700-704 ARE VECTOR- DERIVED

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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: 2.72 Å3/Da / Density % sol: 54.9 % / Description: NONE
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: PROTEIN 4.5 MG/ML IN 20 MM TRIS-HCL PH 8, 100MM NACL, 1MM DTT, 1MM EDTA RESERVOIR 1.75 M SODIUM FORMATE, 0.1 SODIUM CITRATE PH 5.5, 0.15 M POTASSIUM THIOCYANATE VAPOUR DIFFUSION, SITTING DROP, 289 K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Aug 3, 2007 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→18.99 Å / Num. obs: 23524 / % possible obs: 95.4 % / Observed criterion σ(I): 0 / Redundancy: 2.2 % / Biso Wilson estimate: 48 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 11.9
Reflection shellResolution: 2.5→2.64 Å / Redundancy: 2.21 % / Rmerge(I) obs: 0.11 / Mean I/σ(I) obs: 6.6 / % possible all: 93.9

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2IVT, FLEXIBLE LOOPS REMOVED

2ivt


Resolution: 2.5→30 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.908 / SU B: 8.581 / SU ML: 0.194 / Cross valid method: THROUGHOUT / ESU R: 0.508 / ESU R Free: 0.278 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24162 1197 5.1 %RANDOM
Rwork0.20114 ---
obs0.20327 22326 95.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.346 Å2
Baniso -1Baniso -2Baniso -3
1-0.2 Å20.43 Å20.63 Å2
2--0.7 Å21.02 Å2
3----0.22 Å2
Refinement stepCycle: LAST / Resolution: 2.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4327 0 51 45 4423
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0224471
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5621.9836049
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5335559
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.61222.911158
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.28915742
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9521524
X-RAY DIFFRACTIONr_chiral_restr0.0980.2679
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023264
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2110.21951
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3090.23042
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2440.2169
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3080.232
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2010.24
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.791.52897
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.36524490
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.85631844
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.9284.51559
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.564 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.284 80 -
Rwork0.295 1626 -
obs--94.05 %

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