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- PDB-3sd5: Crystal Structure of PI3K gamma with 5-(2,4-dimorpholinopyrimidin... -

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Basic information

Entry
Database: PDB / ID: 3sd5
TitleCrystal Structure of PI3K gamma with 5-(2,4-dimorpholinopyrimidin-6-yl)-4-(trifluoromethyl)pyridin-2-amine
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Lipid Kinase / 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-SD5 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsKnapp, M.S. / Elling, R.A.
CitationJournal: Mol.Cancer Ther. / Year: 2012
Title: Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor.
Authors: Maira, S.M. / Pecchi, S. / Huang, A. / Burger, M. / Knapp, M. / Sterker, D. / Schnell, C. / Guthy, D. / Nagel, T. / Wiesmann, M. / Brachmann, S. / Fritsch, C. / Dorsch, M. / Chene, P. / ...Authors: Maira, S.M. / Pecchi, S. / Huang, A. / Burger, M. / Knapp, M. / Sterker, D. / Schnell, C. / Guthy, D. / Nagel, T. / Wiesmann, M. / Brachmann, S. / Fritsch, C. / Dorsch, M. / Chene, P. / Shoemaker, K. / De Pover, A. / Menezes, D. / Martiny-Baron, G. / Fabbro, D. / Wilson, C.J. / Schlegel, R. / Hofmann, F. / Garcia-Echeverria, C. / Sellers, W.R. / Voliva, C.F.
History
DepositionJun 8, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 4, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 29, 2012Group: Database references
Revision 1.2Sep 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)111,1672
Polymers110,7561
Non-polymers4101
Water19811
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.264, 67.848, 106.633
Angle α, β, γ (deg.)90.00, 96.09, 90.00
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 / 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: Residues 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-SD5 / 5-[2,6-di(morpholin-4-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine


Mass: 410.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21F3N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 11 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsQ459R 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: 2.34 Å3/Da / Density % sol: 47.49 %
Description: THE STRUCTURE FACTOR FILE CONTAIN FRIEDEL PAIRS
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.2M Sodium Acetate, 0.1M Sodium Citrate, 0.1M TRIS pH8.5, 16-19% (w/v)PEG 4000, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9794 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 6, 2006
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9794 Å / Relative weight: 1
ReflectionResolution: 3.2→106 Å / Num. obs: 54055 / % possible obs: 99.1 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 0 / Redundancy: 3.2 % / Biso Wilson estimate: 59.1 Å2 / Rmerge(I) obs: 0.1 / Rsym value: 0.1 / Net I/σ(I): 5.2
Reflection shellResolution: 3.2→3.37 Å / Rmerge(I) obs: 0.319 / Num. unique all: 2369 / % possible all: 99.5

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
PHENIX(phenix.refine: 1.7.1_743)refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3P2B

3p2b


Resolution: 3.2→54.167 Å / SU ML: 0.99 / Cross valid method: THROUGHOUT / σ(F): 1.39 / Phase error: 25.72 / Stereochemistry target values: ML / Details: THE FRIEDEL PAIRS WERE USED FOR PHASING
RfactorNum. reflection% reflectionSelection details
Rfree0.2614 1629 5.06 %RANDOM
Rwork0.2126 ---
obs0.2151 17166 97.02 %-
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 51.157 Å2 / ksol: 0.305 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--4.6118 Å20 Å20.562 Å2
2--6.2017 Å20 Å2
3----1.5899 Å2
Refinement stepCycle: LAST / Resolution: 3.2→54.167 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6380 0 29 11 6420
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0026543
X-RAY DIFFRACTIONf_angle_d0.5968895
X-RAY DIFFRACTIONf_dihedral_angle_d14.4932344
X-RAY DIFFRACTIONf_chiral_restr0.0451029
X-RAY DIFFRACTIONf_plane_restr0.0021145
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.2-3.29430.34621290.28972540X-RAY DIFFRACTION97
3.2943-3.40060.31231230.28042554X-RAY DIFFRACTION97
3.4006-3.52210.36021290.27622537X-RAY DIFFRACTION96
3.5221-3.66310.26421290.24052558X-RAY DIFFRACTION97
3.6631-3.82980.281330.21652539X-RAY DIFFRACTION97
3.8298-4.03160.25311270.21712540X-RAY DIFFRACTION97
4.0316-4.28410.27211480.17922544X-RAY DIFFRACTION97
4.2841-4.61480.21571400.1682569X-RAY DIFFRACTION98
4.6148-5.07890.21721580.1742535X-RAY DIFFRACTION97
5.0789-5.8130.26551430.19472540X-RAY DIFFRACTION97
5.813-7.3210.24141430.21852550X-RAY DIFFRACTION97
7.321-54.17470.24891270.20582529X-RAY DIFFRACTION96
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)
12.8283-0.30340.26451.7056-0.03811.72710.160.4669-0.775-0.27870.14030.07980.27060.07480.07070.35970.0456-0.12290.1925-0.1140.406231.9409-18.570317.9994
21.0681-0.8638-0.53730.8350.24432.0844-0.0925-0.6236-0.55080.16910.02250.28440.299-0.6548-0.37840.1192-0.05070.09790.52650.23510.31646.4575-11.101737.9121
31.7957-0.48410.11461.00850.0341.42670.12010.70520.017-0.23640.0033-0.1942-0.16590.8478-0.0050.37890.05280.12020.822-0.07580.1959.0951-8.467715.1969
42.3917-0.18261.24640.72490.05472.1150.0850.1518-0.1601-0.08270.0633-0.12790.15810.48470.3065-0.04850.11110.1280.0039-0.0028-0.12749.9758-9.925132.4928
52.04820.05680.19441.48380.2121.8563-0.08010.24260.4443-0.06810.05210.3446-0.5008-0.36350.07730.02530.17440.0501-0.0004-0.0681-0.135121.70865.975921.6031
62.6653-0.56011.38431.0663-0.16110.8474-0.3176-0.39490.84650.20180.01540.0414-0.7698-0.3623-0.3530.53360.1509-0.04820.1296-0.07070.338729.479315.377437.4579
73.162-1.26061.08632.3253-0.25312.5396-0.3553-0.40471.03760.05760.0491-0.178-0.7677-0.22960.18360.6419-0.0557-0.14880.3855-0.22440.786538.156619.63237.9671
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resseq 144:208)
2X-RAY DIFFRACTION2chain 'A' and (resseq 209:308)
3X-RAY DIFFRACTION3chain 'A' and (resseq 309:477)
4X-RAY DIFFRACTION4chain 'A' and (resseq 478:688)
5X-RAY DIFFRACTION5chain 'A' and (resseq 689:941)
6X-RAY DIFFRACTION6chain 'A' and (resseq 942:1037)
7X-RAY DIFFRACTION7chain 'A' and (resseq 1038:1092)

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