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- PDB-2x2k: Crystal Structure of phosphorylated RET tyrosine kinase domain wi... -

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Basic information

Entry
Database: PDB / ID: 2x2k
TitleCrystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor
ComponentsPROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
KeywordsTRANSFERASE / TYROSINE KINASE / HIRSCHSPRUNG DISEASE / TYROSINE-PROTEIN KINASE / PROTO-ONCOGENE / PHOSPHOPROTEIN / PHOSPHOTRANSFERASE
Function / homology
Function and homology information


Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / Formation of the ureteric bud ...Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / Formation of the ureteric bud / positive regulation of neuron maturation / Formation of the nephric duct / enteric nervous system development / neuron cell-cell adhesion / innervation / 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 / response to pain / regulation of axonogenesis / homophilic cell adhesion via plasma membrane adhesion molecules / positive regulation of cell size / RET signaling / regulation of cell adhesion / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / axon guidance / receptor protein-tyrosine kinase / positive regulation of neuron projection development / activation of cysteine-type endopeptidase activity involved in apoptotic process / MAPK cascade / retina development in camera-type eye / signaling receptor activity / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / early endosome / receptor complex / endosome membrane / positive regulation of cell migration / response to xenobiotic stimulus / axon / protein phosphorylation / neuronal cell body / calcium ion binding / dendrite / 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 / Cadherin domain / Cadherins domain profile. / Cadherin-like ...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 / Cadherin domain / Cadherins domain profile. / Cadherin-like / Cadherin-like superfamily / 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 / 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-X2K / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 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 1.2Apr 18, 2018Group: Data collection / 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

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1805
Polymers35,7881
Non-polymers3914
Water50428
1
A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)72,35910
Polymers71,5762
Non-polymers7838
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area4050 Å2
ΔGint-19 kcal/mol
Surface area24150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.600, 70.912, 78.871
Angle α, β, γ (deg.)90.00, 101.68, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 35788.215 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN, RESIDUES 705-1013
Source method: isolated from a genetically manipulated source
Details: RESIDUES 705-1013,5 N-TERMINAL VECTOR-DERIVED RESIDUES GPLSL
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.: 3 / Source method: obtained synthetically / Formula: CH2O2
#3: Chemical ChemComp-X2K / (3Z)-5-amino-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one


Mass: 253.299 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H15N3O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / Source method: isolated from a natural source / Formula: H2O
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: 2.9 Å3/Da / Density % sol: 57.7 % / 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 1.85 M SODIUM FORMATE, 0.1 SODIUM CITRATE PH 5.5, 0.2M LITHIUM CHLORIDE 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: Jul 29, 2007 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→21.64 Å / Num. obs: 11886 / % possible obs: 99.1 % / Observed criterion σ(I): 0 / Redundancy: 3.1 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 17
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 3 % / Rmerge(I) obs: 0.23 / Mean I/σ(I) obs: 5.2 / % possible all: 100

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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: 2.6→30 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.884 / SU B: 10.037 / SU ML: 0.216 / Cross valid method: THROUGHOUT / ESU R: 0.524 / ESU R Free: 0.306 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.256 569 4.8 %RANDOM
Rwork0.191 ---
obs0.194 11316 98.9 %-
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: 39.5 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å20 Å20.32 Å2
2--0.69 Å20 Å2
3----0.6 Å2
Refinement stepCycle: LAST / Resolution: 2.6→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2234 0 28 28 2290
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0222317
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6321.9823131
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3755289
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.20123.21887
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.32515395
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.4241513
X-RAY DIFFRACTIONr_chiral_restr0.0990.2346
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021697
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2050.2993
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3050.21551
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1040.273
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1960.249
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0430.24
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7741.51490
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.38722306
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.8253978
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.8714.5824
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: 2.6→2.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 45 -
Rwork0.27 856 -
obs--100 %

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