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- PDB-6no9: PIM1 in complex with Cpd16 (5-amino-N-(5-((4R,5R)-4-amino-5-fluor... -

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Basic information

Entry
Database: PDB / ID: 6no9
TitlePIM1 in complex with Cpd16 (5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide)
ComponentsSerine/threonine-protein kinase pim-1
KeywordsTRANSFERASE / kinase
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 / 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 / regulation of hematopoietic stem cell proliferation / cellular detoxification / 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 / 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-KUV / PHOSPHATE ION / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.712 Å
AuthorsMurray, J.M. / Noland, C.
CitationJournal: J. Med. Chem. / Year: 2019
Title: Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.
Authors: Wang, X. / Blackaby, W. / Allen, V. / Chan, G.K.Y. / Chang, J.H. / Chiang, P.C. / Diene, C. / Drummond, J. / Do, S. / Fan, E. / Harstad, E.B. / Hodges, A. / Hu, H. / Jia, W. / Kofie, W. / ...Authors: Wang, X. / Blackaby, W. / Allen, V. / Chan, G.K.Y. / Chang, J.H. / Chiang, P.C. / Diene, C. / Drummond, J. / Do, S. / Fan, E. / Harstad, E.B. / Hodges, A. / Hu, H. / Jia, W. / Kofie, W. / Kolesnikov, A. / Lyssikatos, J.P. / Ly, J. / Matteucci, M. / Moffat, J.G. / Munugalavadla, V. / Murray, J. / Nash, D. / Noland, C.L. / Del Rosario, G. / Ross, L. / Rouse, C. / Sharpe, A. / Slaga, D. / Sun, M. / Tsui, V. / Wallweber, H. / Yu, S.F. / Ebens, A.J.
History
DepositionJan 15, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)32,2655
Polymers31,5181
Non-polymers7484
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)96.632, 96.632, 80.703
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: 31517.795 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIM1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-KUV / 5-amino-N-{5-[(4R,5R)-4-amino-5-fluoroazepan-1-yl]-1-methyl-1H-pyrazol-4-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide


Mass: 465.495 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22F3N7OS
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 3.45 Å3/Da / Density % sol: 64.36 %
Crystal growTemperature: 292 K / Method: evaporation / pH: 8.5
Details: 0.1 M Tris 8.5, 0.1-0.3M LiSO4, and 29-33% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 18-ID / Wavelength: 0.987 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Mar 25, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.71→58.097 Å / Num. obs: 39434 / % possible obs: 99.8 % / Redundancy: 10.2 % / CC1/2: 1 / Rmerge(I) obs: 0.032 / Rpim(I) all: 0.01 / Rrim(I) all: 0.033 / Net I/σ(I): 33.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.803-1.8098.84.1983820.3591.4864.458100
8.362-58.0979.50.01241710.0040.01399.8

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5V80

5v80


Resolution: 1.712→41.843 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 27.47
RfactorNum. reflection% reflection
Rfree0.2047 1602 5.03 %
Rwork0.1678 --
obs0.1696 31869 69.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 107.71 Å2 / Biso mean: 44.8973 Å2 / Biso min: 23.63 Å2
Refinement stepCycle: final / Resolution: 1.712→41.843 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2211 0 50 146 2407
Biso mean--41.64 48.87 -
Num. residues----273
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7122-1.76750.2998120.34922032155
1.7675-1.83070.3291440.312867571917
1.8307-1.9040.2385550.24351095115028
1.904-1.99060.266810.22271677175842
1.9906-2.09560.24641460.21312695284168
2.0956-2.22690.22271990.20183931413099
2.2269-2.39880.20472130.184639684181100
2.3988-2.64020.24532200.188939754195100
2.6402-3.02210.22532160.179739884204100
3.0221-3.80710.20262040.155740044208100
3.8071-41.85540.17482120.147140564268100
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)
12.4322-2.9323-0.26324.0775-1.83488.610.24390.04111.29530.0643-0.4949-0.3056-0.92130.87250.21840.77110.02260.02980.3208-0.03850.8761-40.15718.78734.1094
20.79850.6617-1.0752.1697-0.0362.24630.03870.23950.501-0.11210.15560.2614-0.7286-0.03180.00090.53570.04030.03980.2607-0.00840.4625-40.33066.37551.9675
30.5365-0.40860.32331.0502-0.14841.0322-0.17190.62380.4024-0.5450.2343-0.8113-0.38661.0122-0.0050.6082-0.07070.14590.4907-0.01050.4972-29.1689-2.9565-7.2781
41.58580.43220.19862.3257-0.18232.14620.0219-0.04840.3821-0.04930.12510.2568-0.5386-0.1022-00.37640.07260.00090.236-0.05430.2978-43.002-3.12454.2255
51.07960.0898-0.37572.53-0.18313.43230.1125-0.13690.0859-0.1378-0.0267-0.0455-0.0870.13480.00020.24990.0456-0.00980.2119-0.03360.2423-39.6952-14.71613.3267
61.64740.5603-0.5182.2459-1.18241.74270.0153-0.26360.00920.1541-0.082-0.33790.11760.54610.00010.30970.0811-0.06060.43340.00020.3365-30.2888-21.349313.0788
72.13640.9726-0.30921.8537-0.69551.7561-0.0226-0.1827-0.2813-0.0616-0.01430.05840.65150.1365-0.00110.37130.0946-0.020.28250.02360.2911-39.951-29.75611.5046
80.41120.1935-0.06350.675-0.65770.9139-0.0945-0.0919-0.3309-0.54850.16490.91460.1808-0.82360.0140.33460.0367-0.00850.53580.00360.491-58.3101-17.92637.6626
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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