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- PDB-4bzn: Crystal structure of PIM1 in complex with a Pyrrolo(1,2-a)Pyrazin... -

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Basic information

Entry
Database: PDB / ID: 4bzn
TitleCrystal structure of PIM1 in complex with a Pyrrolo(1,2-a)Pyrazinone inhibitor
ComponentsSERINE/THREONINE-PROTEIN KINASE PIM-1
KeywordsTRANSFERASE / PIM1 / ATP BINDING / 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
Chem-UGX / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsCasale, E. / Casuscelli, F. / Ardini, E. / Avanzi, N. / Cervi, G. / D'Anello, M. / Donati, D. / Faiardi, D. / Ferguson, R.D. / Fogliatto, G. ...Casale, E. / Casuscelli, F. / Ardini, E. / Avanzi, N. / Cervi, G. / D'Anello, M. / Donati, D. / Faiardi, D. / Ferguson, R.D. / Fogliatto, G. / Galvani, A. / Marsiglio, A. / Mirizzi, D.G. / Montemartini, M. / Orrenius, C. / Papeo, G. / Piutti, C. / Salom, B. / Felder, E.R.
CitationJournal: Bioorg.Med.Chem. / Year: 2013
Title: Discovery and Optimization of Pyrrolo[1,2-A]Pyrazinones Leads to Novel and Selective Inhibitors of Pim Kinases.
Authors: Casuscelli, F. / Ardini, E. / Avanzi, N. / Casale, E. / Cervi, G. / D'Anello, M. / Donati, D. / Faiardi, D. / Ferguson, R.D. / Fogliatto, G. / Galvani, A. / Marsiglio, A. / Mirizzi, D.G. / ...Authors: Casuscelli, F. / Ardini, E. / Avanzi, N. / Casale, E. / Cervi, G. / D'Anello, M. / Donati, D. / Faiardi, D. / Ferguson, R.D. / Fogliatto, G. / Galvani, A. / Marsiglio, A. / Mirizzi, D.G. / Montemartini, M. / Orrenius, C. / Papeo, G. / Piutti, C. / Salom, B. / Felder, E.R.
History
DepositionJul 29, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 30, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2013Group: Database references
Revision 1.2Dec 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_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: SERINE/THREONINE-PROTEIN KINASE PIM-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1812
Polymers35,8361
Non-polymers3451
Water3,063170
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)96.802, 96.802, 79.995
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 SERINE/THREONINE-PROTEIN KINASE PIM-1 / PROTO-ONCOGENE SERINE THREONINE-PROTEIN KINASE PIM-1


Mass: 35835.691 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 2-313
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-UGX / N-(2,2-dimethylpropyl)-2-[1-oxo-7-(thiophen-3-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]acetamide


Mass: 345.459 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H23N3O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 170 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE FIRST TWO RESIDUES AT THE N-TERMINAL GLY AND PRO ARE EXPRESSION TAG

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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: 3.19 Å3/Da / Density % sol: 61.15 % / Description: NONE
Crystal growDetails: 20% PEG 3350K, 0.3 M NACL, 0.1 M TRISHCL PH 7.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.97
DetectorType: MARRESEARCH / Detector: CCD / Date: Apr 29, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. obs: 33517 / % possible obs: 99.7 % / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 12.3
Reflection shellResolution: 1.9→1.97 Å / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 2.7 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1YXT

1yxt


Resolution: 1.9→30 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.958 / SU B: 2.341 / SU ML: 0.07 / Cross valid method: THROUGHOUT / ESU R: 0.113 / ESU R Free: 0.106 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.19879 1699 5.1 %RANDOM
Rwork0.17656 ---
obs0.17766 31804 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.881 Å2
Baniso -1Baniso -2Baniso -3
1-0.2 Å20.1 Å20 Å2
2--0.2 Å20 Å2
3----0.3 Å2
Refinement stepCycle: LAST / Resolution: 1.9→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2228 0 24 170 2422
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192314
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3411.9643145
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0955272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.43223.136118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.45615379
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7041521
X-RAY DIFFRACTIONr_chiral_restr0.0810.2333
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211794
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 110 -
Rwork0.253 2276 -
obs--99.71 %

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