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

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Basic information

Entry
Database: PDB / ID: 3nzs
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 / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / positive regulation of Rac protein signal transduction / regulation of cell adhesion mediated by integrin / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / phosphorylation / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / neutrophil chemotaxis / ephrin receptor binding / 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- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / 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-NZS / 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: 2.75 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)109,7702
Polymers109,3821
Non-polymers3881
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)144.966, 67.965, 106.989
Angle α, β, γ (deg.)90.000, 95.570, 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-NZS / 6-(1,1-dioxidothiomorpholin-4-yl)-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 388.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N6O3S

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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: 2.4 Å3/Da / Density % sol: 48.7 %
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
IDCrystal-ID
11
21
Diffraction source
SourceSiteBeamlineIDWavelength (Å)
SYNCHROTRONALS 5.0.111
SYNCHROTRONALS 5.0.121
Detector
TypeIDDetectorDate
ADSC QUANTUM 3151CCDJul 24, 2007
ADSC QUANTUM 3152CCDApr 10, 2008
Radiation
IDProtocolScattering typeWavelength-ID
1SINGLEx-ray1
2SINGLEx-ray1
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionRedundancy: 8.1 % / Number: 220944 / Rmerge(I) obs: 0.065 / Χ2: 1.06 / D res high: 2.75 Å / D res low: 50 Å / Num. obs: 27142 / % possible obs: 99.3
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squaredRedundancy
5.925099.810.0391.0168
4.75.9210010.041.098.4
4.114.710010.0451.0958.5
3.734.1110010.0611.1598.5
3.463.7310010.0951.2248.5
3.263.4610010.1511.0918.5
3.13.2610010.2521.0418.5
2.963.110010.390.9898.4
2.852.9699.410.5530.937.8
2.752.859410.7070.9026.3
ReflectionResolution: 2.75→50 Å / Num. all: 27142 / Num. obs: 27142 / % possible obs: 99.3 % / Observed criterion σ(I): 2.66 / Redundancy: 8.1 % / Rmerge(I) obs: 0.048

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 38.35
Highest resolutionLowest resolution
Rotation2.75 Å19.97 Å
Translation2.75 Å19.97 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: 2.75→19.973 Å / Occupancy max: 1 / Occupancy min: 0 / FOM work R set: 0.7975 / SU ML: 0.46 / σ(F): 1.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2426 1363 5.05 %
Rwork0.2098 --
obs0.2115 26966 99.38 %
Solvent computationShrinkage radii: 1.06 Å / VDW probe radii: 1.3 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 59.262 Å2 / ksol: 0.291 e/Å3
Displacement parametersBiso max: 257.03 Å2 / Biso mean: 98.2346 Å2 / Biso min: 17.17 Å2
Baniso -1Baniso -2Baniso -3
1-4.3296 Å20 Å23.2702 Å2
2---4.2703 Å2-0 Å2
3----0.0593 Å2
Refinement stepCycle: LAST / Resolution: 2.75→19.973 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6712 0 27 0 6739
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0016898
X-RAY DIFFRACTIONf_angle_d0.4999340
X-RAY DIFFRACTIONf_chiral_restr0.0351055
X-RAY DIFFRACTIONf_plane_restr0.0021179
X-RAY DIFFRACTIONf_dihedral_angle_d10.8132561
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7503-2.84830.37321390.34852428256795
2.8483-2.9620.41051160.32372574269099
2.962-3.09640.36761340.287625362670100
3.0964-3.2590.2911480.257125352683100
3.259-3.46220.2611140.229725972711100
3.4622-3.72790.27951550.21825222677100
3.7279-4.10010.21451270.194426002727100
4.1001-4.68670.20491530.161325632716100
4.6867-5.87970.23291440.193625882732100
5.8797-19.97340.20251330.195526602793100
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)
13.86040.19012.26721.43690.60081.88020.11051.7519-1.7513-0.30540.1965-0.29680.37230.6192-0.38560.38590.1965-0.15890.7812-0.54810.856637.6804-18.935411.6009
23.043-1.30260.61531.38520.45222.69520.1451-0.8303-1.33680.31220.27290.81970.1464-1.3994-0.5340.35330.03830.22040.95440.55550.990110.462-11.849836.3181
32.68950.23292.50051.9788-1.71536.09940.06071.6959-0.496-0.1309-0.2794-0.385-0.16292.87960.05290.21720.05140.04311.6802-0.20230.21463.9138-5.260313.9273
43.6810.39381.35980.936-0.02290.90890.19521.7722-0.2247-0.3704-0.2346-0.079-0.03481.3717-0.22920.44880.25430.09561.1706-0.28660.166855.4018-6.403412.4076
56.2653-1.1052.88780.8449-0.1564.20470.2165-0.1708-0.9280.10010.19270.20590.010.2191-0.32250.25020.0116-0.00210.12670.0290.271246.1045-10.459934.1653
64.5168-2.04810.14262.56840.41620.68330.39271.4114-0.4824-0.5575-0.3280.7484-0.2094-0.7569-0.2230.43090.2921-0.07640.81530.15560.41216.61794.442211.7125
71.6322-0.44120.71940.99820.01240.4195-0.4090.18280.56411.28070.2210.1954-0.6299-0.64120.12870.98130.25540.24330.35010.00640.399329.19814.734634.752
84.0107-0.95730.61033.5163-0.72340.21220.09861.22531.14940.9512-0.1367-0.3456-0.43210.2890.11890.4830.19110.03680.65960.10860.401526.54665.008218.4762
97.824-0.74880.87832.5785-0.6351.3345-0.7816-0.47552.07551.30760.2509-0.0503-0.778-0.17370.33781.01390.2584-0.07520.2175-0.12110.681429.189418.881936.885
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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