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- PDB-3nzu: Structure-based Optimization of Pyrazolo -Pyrimidine and -Pyridin... -

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Basic information

Entry
Database: PDB / ID: 3nzu
TitleStructure-based Optimization of Pyrazolo -Pyrimidine and -Pyridine Inhibitors of PI3-Kinase
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase p110 / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of triglyceride catabolic process / secretory granule localization / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis ...negative regulation of triglyceride catabolic process / secretory granule localization / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / dendritic cell chemotaxis / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / mast cell degranulation / hepatocyte apoptotic process / positive regulation of Rac protein signal transduction / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / phosphorylation / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / ephrin receptor binding / neutrophil chemotaxis / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of endothelial cell migration / T cell activation / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / kinase activity / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / angiogenesis / adaptive immune response / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / protein kinase activity / inflammatory response / immune response / G protein-coupled receptor signaling pathway / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / identical protein binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / C2 domain superfamily / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Ubiquitin-like (UB roll) / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Roll / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-NZU / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.6 Å
AuthorsMurray, J.M. / Wiesmann, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Structure-based optimization of pyrazolo-pyrimidine and -pyridine inhibitors of PI3-kinase.
Authors: Staben, S.T. / Heffron, T.P. / Sutherlin, D.P. / Bhat, S.R. / Castanedo, G.M. / Chuckowree, I.S. / Dotson, J. / Folkes, A.J. / Friedman, L.S. / Lee, L. / Lesnick, J. / Lewis, C. / Murray, J. ...Authors: Staben, S.T. / Heffron, T.P. / Sutherlin, D.P. / Bhat, S.R. / Castanedo, G.M. / Chuckowree, I.S. / Dotson, J. / Folkes, A.J. / Friedman, L.S. / Lee, L. / Lesnick, J. / Lewis, C. / Murray, J.M. / Nonomiya, J. / Olivero, A.G. / Plise, E. / Pang, J. / Prior, W.W. / Salphati, L. / Rouge, L. / Sampath, D. / Tsui, V. / Wan, N.C. / Wang, S. / Wiesmann, C. / Wu, P. / Zhu, B.Y.
History
DepositionJul 16, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 29, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,7672
Polymers109,3821
Non-polymers3851
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.004, 67.677, 106.362
Angle α, β, γ (deg.)90.000, 95.520, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform / PtdIns-3-kinase subunit gamma / PI3-kinase subunit gamma / PI3K-gamma / Phosphatidylinositol-4 / 5- ...PtdIns-3-kinase subunit gamma / PI3-kinase subunit gamma / PI3K-gamma / Phosphatidylinositol-4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p120-PI3K


Mass: 109381.617 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: pik3cg / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-NZU / 6-(2H-indazol-4-yl)-1-methyl-N-[3-(methylsulfonyl)propyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 385.443 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H19N7O2S

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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: 2.36 Å3/Da / Density % sol: 47.84 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: PEG 3350, 0.2M NH4SO4, 0.1M Tris-HCl 8.5, vapor diffusion, hanging drop, temperature 289K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 10, 2008
RadiationProtocol: SINGLE / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 31733 / % possible obs: 99.9 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.049 / Χ2: 1.069 / Net I/σ(I): 17.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.6-2.693.80.59231321.055100
2.69-2.83.80.40831541.106100
2.8-2.933.80.28931601.187100
2.93-3.083.80.18131711.188100
3.08-3.283.80.11431381.10599.9
3.28-3.533.80.07631651.081100
3.53-3.883.70.05631730.983100
3.88-4.453.70.04831970.96899.9
4.45-5.63.60.03632001.02299.8
5.6-503.60.02832430.98599.1

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 36.81
Highest resolutionLowest resolution
Rotation2.6 Å19.88 Å
Translation2.6 Å19.88 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.1.4phasing
PHENIXdev_392refinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→19.88 Å / Occupancy max: 1 / Occupancy min: 0 / FOM work R set: 0.7882 / SU ML: 0.32 / σ(F): 1.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2405 1587 5.04 %
Rwork0.2129 --
obs0.2143 31490 99.86 %
Solvent computationShrinkage radii: 1.01 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 65.822 Å2 / ksol: 0.319 e/Å3
Displacement parametersBiso max: 287.7 Å2 / Biso mean: 97.2593 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1-2.2044 Å20 Å21.8965 Å2
2---4.7139 Å20 Å2
3---2.5095 Å2
Refinement stepCycle: LAST / Resolution: 2.6→19.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6670 0 27 0 6697
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0026821
X-RAY DIFFRACTIONf_angle_d0.4739239
X-RAY DIFFRACTIONf_chiral_restr0.0341042
X-RAY DIFFRACTIONf_plane_restr0.0011169
X-RAY DIFFRACTIONf_dihedral_angle_d10.8462527
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.6001-2.68380.36641270.29726952822100
2.6838-2.77950.32891400.293627002840100
2.7795-2.89050.36481270.296527232850100
2.8905-3.02160.32811690.268526802849100
3.0216-3.18030.31231590.274627022861100
3.1803-3.37860.27421210.250127242845100
3.3786-3.6380.28891550.231627122867100
3.638-4.00150.22451450.20227322877100
4.0015-4.57430.19791530.173426942847100
4.5743-5.74010.22191480.188127622910100
5.7401-19.88060.19941430.19532779292299
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)
13.9259-0.60380.84552.19511.11461.5431-0.12321.4927-1.2021-0.31030.3019-0.00680.44610.0707-0.23380.52040.0709-0.16690.768-0.35970.918837.3337-18.113412.0597
22.3397-0.14650.29380.88660.6212.23870.1993-0.6451-0.93530.01380.2150.65010.086-1.1506-0.43850.52290.07670.21331.15350.57951.030710.6114-10.363636.2178
32.22740.47280.18871.458-0.78372.54420.01470.4937-0.1563-0.2398-0.1665-0.2657-0.15111.37090.10470.44170.0137-0.00221.0053-0.090.379763.5211-4.574413.3277
40.8270.934-0.50221.0314-0.54990.2892-0.12581.32540.3936-0.36150.06190.0461-0.34841.0351-0.0130.54630.13920.0461.1149-0.09540.408454.3389-3.172210.6004
55.5038-0.85982.22871.27990.04673.44380.1954-0.3328-0.75160.13510.14960.15710.0490.2364-0.27210.32580.0217-0.00270.30620.05720.315245.7555-9.574934.0976
64.4201-2.23850.62122.2397-0.64090.71290.2951.2223-0.4401-0.2023-0.10390.7753-0.1257-0.4779-0.28630.52890.1694-0.02980.89820.18180.557416.63815.469111.7669
71.7743-0.72131.21332.6631-1.18421.0297-0.1119-0.08770.30191.24520.32160.4699-1.2718-0.9328-0.10630.72450.21070.17230.43530.04780.42929.17095.669834.526
82.33810.30960.22462.6352-1.05981.6651-0.15120.76850.5641.08440.0673-0.1765-0.79830.50340.24150.54320.10150.03620.61690.08410.294326.41785.899918.3677
96.4357-0.0431.09021.1936-1.10841.5498-0.6961-0.67051.55091.10510.2931-0.1168-1.2227-0.16630.27421.27450.3303-0.07040.4677-0.15270.693429.44919.825936.2385
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 144:190)A144 - 190
2X-RAY DIFFRACTION2(chain A and resid 191:321)A191 - 321
3X-RAY DIFFRACTION3(chain A and resid 350:488)A350 - 488
4X-RAY DIFFRACTION4(chain A and resid 495:533)A495 - 533
5X-RAY DIFFRACTION5(chain A and resid 544:725)A544 - 725
6X-RAY DIFFRACTION6(chain A and resid 726:836)A726 - 836
7X-RAY DIFFRACTION7(chain A and resid 837:866)A837 - 866
8X-RAY DIFFRACTION8(chain A and resid 867:881)A867 - 881
9X-RAY DIFFRACTION9(chain A and resid 882:1090)A882 - 1090

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