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- PDB-3tjp: Crystal Structure of PI3K gamma with N6-(3,4-dimethoxyphenyl)-2-m... -

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Basic information

Entry
Database: PDB / ID: 3tjp
TitleCrystal Structure of PI3K gamma with N6-(3,4-dimethoxyphenyl)-2-morpholino-[4,5'-bipyrimidine]-2',6-diamine
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Multi-Domain / Lipid Kinase cell signaling / 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-13K / 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: 2.7 Å
AuthorsKnapp, M.S. / Elling, R.A. / Ornelas, E.
CitationJournal: To be Published
Title: The Identification of 5-(2,4-dimorpholinopyrimidin-6-yl)-4-(trifluoromethyl)pyridin-2-amine (NVP-BKM120) as a Potent, Selective and Orally Bioavailable Class I PI3 Kinase Inhibitor for the Treatment of Cancer
Authors: Burger, M.T. / Pecchi, S. / Wagman, A. / Ni, Z.-J. / Knapp, M.S. / Hendrickson, T. / Atallah, G. / Pfister, K. / Yanchen, Z. / Bartulis, S. / Frazier, K. / Ng, S. / Smith, A. / Verhagen, J. ...Authors: Burger, M.T. / Pecchi, S. / Wagman, A. / Ni, Z.-J. / Knapp, M.S. / Hendrickson, T. / Atallah, G. / Pfister, K. / Yanchen, Z. / Bartulis, S. / Frazier, K. / Ng, S. / Smith, A. / Verhagen, J. / Haznedar, J. / Huh, K. / Iwanowicz, E. / Xin, X. / Menezes, D. / Merritt, H. / Lee, I. / Weisman, M. / Kaufman, S. / Crawford, K. / Chin, M. / Bussiere, D. / Shoemaker, K. / Zaror, I. / Maira, M. / Voliva, C.
History
DepositionAug 24, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 29, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)111,2623
Polymers110,7561
Non-polymers5062
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.145, 67.395, 106.180
Angle α, β, γ (deg.)90.00, 96.49, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-13-

HOH

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Components

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


Mass: 110756.164 Da / Num. of mol.: 1 / Fragment: UNP residues 144-1102 / Mutation: Q459R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-13K / N~6~-(3,4-dimethoxyphenyl)-2-(morpholin-4-yl)-4,5'-bipyrimidine-2',6-diamine


Mass: 409.442 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23N7O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsQ TO R SEQUENCE CONFLICT IN UNP ENTRY P48736

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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: 2.28 Å3/Da / Density % sol: 46.08 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 16-19% PEG 4000, 0.2M SODIUM ACETATE,0.1M SODIUM CITRATE, 0.1M TRIS PH 8.5, PROTEIN at 6MG/ML IN 20MM TRIS PH 7.2, 50MM AMMSO4, 1% BETAINE, 1% ETHYLENE GLYCOL, 0.02% CHAPS, 5MM DTT, VAPOR ...Details: 16-19% PEG 4000, 0.2M SODIUM ACETATE,0.1M SODIUM CITRATE, 0.1M TRIS PH 8.5, PROTEIN at 6MG/ML IN 20MM TRIS PH 7.2, 50MM AMMSO4, 1% BETAINE, 1% ETHYLENE GLYCOL, 0.02% CHAPS, 5MM DTT, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jun 1, 2005
RadiationMonochromator: Double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.7→105.499 Å / Num. all: 30574 / Num. obs: 27401 / % possible obs: 98.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1 / Redundancy: 3.9 % / Rmerge(I) obs: 0.068 / Rsym value: 0.068 / Net I/σ(I): 17.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.7-2.853.20.5771.21189637190.57793.2
2.85-3.024.10.3951.81557638270.395100
3.02-3.234.10.2412.21465335720.241100
3.23-3.4940.1573.71339233250.157100
3.49-3.8240.0976.21238330620.097100
3.82-4.2740.0728.51113727770.072100
4.27-4.934.10.05510.91009524880.055100
4.93-6.0440.05311.2844320940.053100
6.04-8.5440.04910.9644816220.04999.9
8.54-105.4093.70.04811.134139150.04898

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.2.5data scaling
PHASERphasing
PHENIX1.7.1_743refinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3P2B

3p2b


Resolution: 2.7→51.618 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.76 / Cross valid method: THROUGHOUT / σ(F): 1.16 / Phase error: 30.79 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2659 2658 5.02 %RANDOM
Rwork0.21 ---
obs0.213 27401 98.53 %-
all-30574 --
Solvent computationShrinkage radii: 0.72 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 73.738 Å2 / ksol: 0.319 e/Å3
Displacement parametersBiso max: 281.79 Å2 / Biso mean: 104.4745 Å2 / Biso min: 38.34 Å2
Baniso -1Baniso -2Baniso -3
1-3.3385 Å20 Å22.9064 Å2
2--3.5321 Å2-0 Å2
3----6.8706 Å2
Refinement stepCycle: LAST / Resolution: 2.7→51.618 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6542 0 35 31 6608
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0026715
X-RAY DIFFRACTIONf_angle_d0.5849127
X-RAY DIFFRACTIONf_chiral_restr0.0431052
X-RAY DIFFRACTIONf_plane_restr0.0021162
X-RAY DIFFRACTIONf_dihedral_angle_d11.552404
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 19

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7-2.74910.47151070.34272288239585
2.7491-2.8020.331400.3262554269492
2.802-2.85920.3791270.3032570269798
2.8592-2.92130.36641270.283627682895100
2.9213-2.98930.31291570.25225932750100
2.9893-3.0640.31151320.249427042836100
3.064-3.14690.32051490.249127312880100
3.1469-3.23950.33981590.255826192778100
3.2395-3.3440.28841290.240926882817100
3.344-3.46350.3091540.227726802834100
3.4635-3.60210.27091120.215727032815100
3.6021-3.7660.27881250.200827492874100
3.766-3.96450.27431460.207826772823100
3.9645-4.21280.27091620.194426422804100
4.2128-4.53790.26521460.17726632809100
4.5379-4.99420.22761320.179127072839100
4.9942-5.71610.30291480.206226972845100
5.7161-7.19860.28331520.233826652817100
7.1986-51.62720.1851540.18092639279399
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)
12.6934-0.16460.23481.1162-0.03262.71350.09980.0273-0.31320.06610.03830.37230.0659-0.2762-0.05680.55080.0705-0.05750.2959-0.03670.462531.4055-11.973623.8994
24.5812-0.71010.9160.8571-0.2993.91040.16540.2926-0.533-0.09820.01670.020.00540.5704-0.04610.3171-0.00250.05890.1845-0.05930.268245.1662-9.055426.08
34.0425-1.13991.22164.28120.38633.0539-0.17460.21940.8940.2608-0.07820.2407-0.7046-0.70170.12630.62870.17240.01060.58550.09250.662718.680311.70924.7561
42.3683-0.33780.76572.28880.06240.2703-0.2993-0.47011.09620.3897-0.17340.0055-0.8953-0.2460.20331.08540.0378-0.17210.5197-0.14010.679333.510616.989339.0155
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq 144:427)A0
2X-RAY DIFFRACTION2chain 'A' and (resseq 428:752)A0
3X-RAY DIFFRACTION3chain 'A' and (resseq 753:965)A0
4X-RAY DIFFRACTION4chain 'A' and (resseq 966:1092)A0

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