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- PDB-4k1b: Structure of PIM-1 kinase bound to N-(5-(2-fluorophenyl)-1H-pyrro... -

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Basic information

Entry
Database: PDB / ID: 4k1b
TitleStructure of PIM-1 kinase bound to N-(5-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-((((3R,4R)-3-fluoropiperidin-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide
ComponentsSerine/threonine-protein kinase pim-1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PIM-1 / kinase domain / Ser/Thr kinase / ATP-competitive / structure-based drug design / phosphorylation / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of cardioblast proliferation / regulation of hematopoietic stem cell proliferation / cellular detoxification / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / transcription factor binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / ribosomal small subunit binding / positive regulation of cardiac muscle cell proliferation / positive regulation of TORC1 signaling ...positive regulation of cardioblast proliferation / regulation of hematopoietic stem cell proliferation / cellular detoxification / vitamin D receptor signaling pathway / STAT5 activation downstream of FLT3 ITD mutants / transcription factor binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / ribosomal small subunit binding / positive regulation of cardiac muscle cell proliferation / positive regulation of TORC1 signaling / Signaling by FLT3 fusion proteins / negative regulation of innate immune response / positive regulation of brown fat cell differentiation / 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 / cytoplasm / cytosol
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-1OC / PHOSPHATE ION / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.082 Å
AuthorsMurray, J.M. / Wallweber, H. / Steffek, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design.
Authors: Wang, X. / Magnuson, S. / Pastor, R. / Fan, E. / Hu, H. / Tsui, V. / Deng, W. / Murray, J. / Steffek, M. / Wallweber, H. / Moffat, J. / Drummond, J. / Chan, G. / Harstad, E. / Ebens, A.J.
History
DepositionApr 4, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2013Provider: repository / Type: Initial release
Revision 1.1May 22, 2013Group: 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

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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)32,1153
Polymers31,5181
Non-polymers5972
Water2,288127
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)97.993, 97.993, 80.542
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65

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Components

#1: Protein Serine/threonine-protein kinase pim-1 / PIM-1 kinase


Mass: 31517.795 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 124-396)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIM-1, PIM1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-1OC / N-[5-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-5-({[(3R,4R)-3-fluoropiperidin-4-yl]methyl}amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 502.519 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H24F2N8O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 127 / Source method: isolated from a natural source / Formula: H2O

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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: 3.54 Å3/Da / Density % sol: 65.27 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: PEG4000, 0.2 M lithium sulfate, 0.1 M Tris-HCl, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.977 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 5, 2012
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionResolution: 2.082→80.542 Å / Num. all: 26448 / Num. obs: 26448 / % possible obs: 100 % / Redundancy: 7.4 % / Rsym value: 0.036 / Net I/σ(I): 33.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.082-2.197.50.511.52879038460.51100
2.19-2.337.50.3162.52723736480.316100
2.33-2.497.50.2023.92552734010.202100
2.49-2.697.50.1296.12405531970.129100
2.69-2.947.50.07210.92199629310.072100
2.94-3.297.50.03919.41981626480.039100
3.29-3.87.40.02429.21738323530.024100
3.8-4.657.30.01834.61455019990.018100
4.65-6.587.30.01537.61132115550.015100
6.58-80.5427.10.01253.662208700.01299.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASERphasing
PHENIX1.8_1068refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.082→48.996 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8894 / SU ML: 0.21 / σ(F): 1.93 / Phase error: 18.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1988 1336 5.06 %
Rwork0.1706 --
obs0.172 26415 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 113.74 Å2 / Biso mean: 44.2614 Å2 / Biso min: 19.45 Å2
Refinement stepCycle: LAST / Resolution: 2.082→48.996 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2205 0 42 127 2374
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042316
X-RAY DIFFRACTIONf_angle_d0.9423149
X-RAY DIFFRACTIONf_chiral_restr0.068333
X-RAY DIFFRACTIONf_plane_restr0.003408
X-RAY DIFFRACTIONf_dihedral_angle_d14.091839
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.082-2.1560.27341380.22724762614
2.156-2.24240.24361260.21725172643
2.2424-2.34440.2581350.205324882623
2.3444-2.4680.20921240.196825082632
2.468-2.62260.24251510.189724782629
2.6226-2.82510.21991270.195525102637
2.8251-3.10940.22361310.182825142645
3.1094-3.55920.20151410.168625012642
3.5592-4.48370.17571340.143825322666
4.4837-49.01010.16481290.158225552684
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.8767-0.6087-0.50685.9887-0.70922.12450.22060.20191.0311-0.2932-0.49080.20380.05161.4786-0.08970.83780.00850.08330.5069-0.03170.7574-41.12599.1255-5.5329
25.88141.1369-0.18436.9714-0.46075.9233-0.5117-0.22590.28460.00090.55710.4456-1.0547-0.07550.00810.50260.05490.02160.2392-0.06470.2952-40.78816.0842-7.4131
32.10463.14990.10557.1887-0.4446.6971-0.47240.8831-0.024-1.26970.3448-0.9374-0.09971.3687-0.13290.5428-0.04510.13870.5253-0.04370.3973-29.5206-3.4515-16.3541
42.20680.3406-0.67264.1246-1.29773.11090.0346-0.10360.21450.00750.13490.3757-0.5203-0.0156-0.16140.4320.0632-0.01260.2853-0.0320.2802-43.4018-3.615-4.9504
53.279-0.4434-0.88292.2076-0.3532.9430.219-0.08750.1037-0.1877-0.0187-0.0004-0.31940.1218-0.17620.29640.0049-0.01370.2129-0.04640.2063-40.0407-15.2066-5.9362
63.9947-0.0633-1.71632.9881-1.6794.22160.0718-0.4660.10830.2845-0.0125-0.33560.01330.7258-0.05850.26920.0051-0.05280.3452-0.04580.2745-30.8256-22.1013.7942
73.0416-0.3162-0.55522.377-0.49044.3690.0241-0.0339-0.4945-0.13690.040.1140.44960.2187-0.06520.270.0482-0.05140.2254-0.01270.3628-40.5359-30.37041.998
86.48970.1376-0.48059.35360.13329.02610.113-0.3692-0.5118-0.54660.2791.5973-0.4885-1.1814-0.34580.23860.0311-0.05840.49650.11090.5227-58.7911-18.2838-1.7495
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq 33:49)A33 - 49
2X-RAY DIFFRACTION2chain 'A' and (resseq 50:73)A50 - 73
3X-RAY DIFFRACTION3chain 'A' and (resseq 74:96)A74 - 96
4X-RAY DIFFRACTION4chain 'A' and (resseq 97:140)A97 - 140
5X-RAY DIFFRACTION5chain 'A' and (resseq 141:204)A141 - 204
6X-RAY DIFFRACTION6chain 'A' and (resseq 205:250)A205 - 250
7X-RAY DIFFRACTION7chain 'A' and (resseq 251:290)A251 - 290
8X-RAY DIFFRACTION8chain 'A' and (resseq 291:305)A291 - 305

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