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- PDB-5v82: PIM1 kinase in complex with Cpd17 (1-(6-(4,4-difluoropiperidin-3-... -

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Basic information

Entry
Database: PDB / ID: 5v82
TitlePIM1 kinase in complex with Cpd17 (1-(6-(4,4-difluoropiperidin-3-yl)pyridin-2-yl)-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine)
ComponentsSerine/threonine-protein kinase pim-1
KeywordsTRANSFERASE/INHIBITOR / PIM1 / SBDD / TRANSFERASE-INHIBITOR complex
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 / transcription factor binding / ribosomal small subunit 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 / transcription factor binding / ribosomal small subunit 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 / 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 / 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-96Y / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.888 Å
AuthorsMurray, J.M. / Wallweber, H.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability.
Authors: Wang, X. / Kolesnikov, A. / Tay, S. / Chan, G. / Chao, Q. / Do, S. / Drummond, J. / Ebens, A.J. / Liu, N. / Ly, J. / Harstad, E. / Hu, H. / Moffat, J. / Munugalavadla, V. / Murray, J. / ...Authors: Wang, X. / Kolesnikov, A. / Tay, S. / Chan, G. / Chao, Q. / Do, S. / Drummond, J. / Ebens, A.J. / Liu, N. / Ly, J. / Harstad, E. / Hu, H. / Moffat, J. / Munugalavadla, V. / Murray, J. / Slaga, D. / Tsui, V. / Volgraf, M. / Wallweber, H. / Chang, J.H.
History
DepositionMar 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2017Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)34,8552
Polymers34,4471
Non-polymers4071
Water2,558142
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)96.485, 96.485, 80.628
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


Mass: 34447.141 Da / Num. of mol.: 1 / Fragment: UNP residues 29-313
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIM1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-96Y / 1-{6-[(3R)-4,4-difluoropiperidin-3-yl]pyridin-2-yl}-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine


Mass: 407.419 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19F2N7
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 142 / 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: 3.44 Å3/Da / Density % sol: 64.23 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1 M Tris 8.5, LiSO4, PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Mar 14, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.833→41.779 Å / Num. obs: 37600 / % possible obs: 100 % / Redundancy: 10.1 % / CC1/2: 1 / Rmerge(I) obs: 0.035 / Rpim(I) all: 0.011 / Rrim(I) all: 0.037 / Net I/σ(I): 29.8
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) all
1.833-1.8399.10.8680.8480.3020.92
8.504-80.659.40.01710.0060.018

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
PHENIX1.7.3_928refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.888→41.779 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19
RfactorNum. reflection% reflection
Rfree0.1986 1731 5.05 %
Rwork0.1815 --
obs0.1824 34245 99.82 %
Solvent computationShrinkage radii: 0.86 Å / VDW probe radii: 1.1 Å / Bsol: 45.531 Å2 / ksol: 0.384 e/Å3
Displacement parametersBiso max: 120.08 Å2 / Biso mean: 43.0209 Å2 / Biso min: 22.26 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 1.888→41.779 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2223 0 30 142 2395
Biso mean--35.31 47.08 -
Num. residues----273
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072333
X-RAY DIFFRACTIONf_angle_d1.0253171
X-RAY DIFFRACTIONf_chiral_restr0.076334
X-RAY DIFFRACTIONf_plane_restr0.005412
X-RAY DIFFRACTIONf_dihedral_angle_d13.788852
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8879-1.94350.34151630.289526722835100
1.9435-2.00620.2791220.249327172839100
2.0062-2.07790.27381550.215826852840100
2.0779-2.16110.21941270.194927182845100
2.1611-2.25940.19281390.177627262865100
2.2594-2.37850.20781390.1727132852100
2.3785-2.52750.22161360.189727112847100
2.5275-2.72270.20471560.191426842840100
2.7227-2.99660.2261320.181327412873100
2.9966-3.430.19961570.187426862843100
3.43-4.32080.17981570.165727072864100
4.3208-41.78940.17191480.17092754290299
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)
10.13990.0693-0.06120.4020.65581.41680.0439-0.36740.62730.08920.2141-0.1588-0.04150.44670.34580.3126-0.1919-0.03850.5049-0.07010.6399-12.472839.4483-3.7662
20.13960.01310.14231.09140.70970.67280.16570.020.09010.3478-0.0417-0.51420.06670.60090.20120.2067-0.0780.02430.3462-0.00490.3631-14.764137.6314-5.3732
30.2768-0.29320.0521.1-0.83090.8002-0.00610.3692-0.4637-0.54990.438-0.13410.3070.12090.31490.4007-0.04970.08210.515-0.22710.437-17.575323.9361-15.0154
40.3670.2061-0.03330.1273-0.11610.44310.075-0.05630.25940.1091-0.0525-0.0659-0.25350.197600.3237-0.06020.01560.3593-0.03510.3295-24.273535.7082-3.0385
50.34930.19510.40630.337-0.02090.7774-0.0215-0.00940.043-0.12190.12980.0594-0.04030.084300.2784-0.0393-0.00380.2808-0.03750.2811-32.687527.0751-3.9302
60.59850.3246-0.33610.3243-0.13230.1795-0.063-0.1403-0.13670.27220.10910.10810.36080.07530.00010.41960.0214-0.0390.2876-0.00290.2788-33.637215.6685.862
70.4122-0.1392-0.10790.3655-0.00880.3149-0.12670.0581-0.14470.06460.08240.37480.2625-0.33930.00010.3434-0.05240.00250.28980.01480.3119-45.7419.79934.4866
81.43580.578-0.66260.5107-0.03230.57090.00310.60910.3527-0.1290.35490.5846-0.6421-0.280.0860.44830.0430.02610.27480.00460.4544-44.620141.68290.664
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq 34:49)A34 - 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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