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- PDB-4a7c: Crystal structure of PIM1 kinase with ETP46546 -

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Basic information

Entry
Database: PDB / ID: 4a7c
TitleCrystal structure of PIM1 kinase with ETP46546
ComponentsPROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE PIM-1
KeywordsTRANSFERASE / PROTEIN KINASE / INHIBITOR
Function / homology
Function and homology information


positive regulation of cardioblast proliferation / cellular detoxification / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / ribosomal small subunit binding / transcription factor binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of cardiac muscle cell proliferation / positive regulation of TORC1 signaling ...positive regulation of cardioblast proliferation / cellular detoxification / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / ribosomal small subunit binding / transcription factor binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of cardiac muscle cell proliferation / positive regulation of TORC1 signaling / Signaling by FLT3 fusion proteins / positive regulation of brown fat cell differentiation / negative regulation of innate immune response / protein serine/threonine kinase activator activity / regulation of transmembrane transporter activity / positive regulation of protein serine/threonine kinase activity / negative regulation of DNA-binding transcription factor activity / cellular response to type II interferon / manganese ion binding / Interleukin-4 and Interleukin-13 signaling / protein autophosphorylation / protein stabilization / non-specific serine/threonine protein kinase / cell cycle / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / nucleolus / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Serine/threonine-protein kinase pim-1/2/3 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Serine/threonine-protein kinase pim-1/2/3 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / 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
ACETATE ION / Chem-E46 / IMIDAZOLE / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsMazzorana, M. / Montoya, G.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Hit to Lead Evaluation of 1,2,3-Triazolo[4,5-B]Pyridines as Pim Kinase Inhibitors.
Authors: Pastor, J. / Oyarzabal, J. / Saluste, G. / Alvarez, R.M. / Rivero, V. / Ramos, F. / Cendon, E. / Blanco-Aparicio, C. / Ajenjo, N. / Cebria, A. / Albarran, M.I. / Cebrian, D. / Corrionero, A. ...Authors: Pastor, J. / Oyarzabal, J. / Saluste, G. / Alvarez, R.M. / Rivero, V. / Ramos, F. / Cendon, E. / Blanco-Aparicio, C. / Ajenjo, N. / Cebria, A. / Albarran, M.I. / Cebrian, D. / Corrionero, A. / Fominaya, J. / Montoya, G. / Mazzorana, M.
History
DepositionNov 12, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 15, 2012Provider: repository / Type: Initial release
Revision 1.1May 23, 2012Group: Other
Revision 1.2Jan 14, 2015Group: Non-polymer description
Revision 1.3Dec 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_conn / 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_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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 SERINE/THREONINE-PROTEIN KINASE PIM-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9664
Polymers35,4451
Non-polymers5213
Water3,423190
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.355, 99.355, 81.119
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

#1: Protein PROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE PIM-1 / PIM1


Mass: 35445.070 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 434-717
Source method: isolated from a genetically manipulated source
Details: PHOSPHORYLATED AT SER 261 / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): ROSETTA PLYSS
References: UniProt: P11309, EC: 2.7.1.37, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-E46 / N-(piperidin-4-ylmethyl)-3-[3-(trifluoromethyloxy)phenyl]-[1,2,3]triazolo[4,5-b]pyridin-5-amine


Mass: 392.378 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19F3N6O
#3: Chemical ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#4: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 190 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsGENE ACCORDING TO ORIGENE ACCESSION NUMBER NM_002648 UNIPROT ISOFORM 2

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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: 3.21 Å3/Da / Density % sol: 61.69 % / Description: NONE
Crystal growpH: 7 / Details: 0.1 M IMIDAZOLE PH 7.0, 1 M NA ACETATE.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 27, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.3→49.68 Å / Num. obs: 20344 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 7.6 % / Biso Wilson estimate: 30.9 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 16.8
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 7.6 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 4.8 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1YXT

1yxt


Resolution: 2.3→49.678 Å / SU ML: 0.24 / σ(F): 0.04 / Phase error: 19.64 / Stereochemistry target values: ML / Details: DISORDERED N-TERMINUS AND PART OF GLU 32
RfactorNum. reflection% reflection
Rfree0.2072 1015 5.1 %
Rwork0.1689 --
obs0.1709 19934 97.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 29.444 Å2 / ksol: 0.335 e/Å3
Displacement parametersBiso mean: 28.59 Å2
Baniso -1Baniso -2Baniso -3
1-1.027 Å20 Å20 Å2
2--1.027 Å20 Å2
3----2.0541 Å2
Refinement stepCycle: LAST / Resolution: 2.3→49.678 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2232 0 37 190 2459
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072331
X-RAY DIFFRACTIONf_angle_d1.1343166
X-RAY DIFFRACTIONf_dihedral_angle_d18.668849
X-RAY DIFFRACTIONf_chiral_restr0.071334
X-RAY DIFFRACTIONf_plane_restr0.004409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.42130.25461450.19722620X-RAY DIFFRACTION95
2.4213-2.5730.22041420.18752654X-RAY DIFFRACTION97
2.573-2.77160.24811520.18782656X-RAY DIFFRACTION97
2.7716-3.05050.23331520.17872696X-RAY DIFFRACTION99
3.0505-3.49180.1981440.16682720X-RAY DIFFRACTION99
3.4918-4.39890.17231350.14582777X-RAY DIFFRACTION100
4.3989-49.68910.18831450.15542796X-RAY DIFFRACTION99

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