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- PDB-3t8m: Rational Design of PI3K-alpha Inhibitors that Exhibit Selectivity... -

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Basic information

Entry
Database: PDB / ID: 3t8m
TitleRational Design of PI3K-alpha Inhibitors that Exhibit Selectivity Over the PI3K-beta Isoform
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


secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / 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-kinase complex, class IA / 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 / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / T cell activation / ephrin receptor binding / neutrophil chemotaxis / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / Signaling by CSF1 (M-CSF) in myeloid cells / kinase activity / 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 / immune response / inflammatory response / G protein-coupled receptor signaling pathway / phosphorylation / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / ATP binding / membrane / identical protein binding / 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. / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain / C2 phosphatidylinositol 3-kinase-type domain / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / 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-3T8 / 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: 2.5 Å
AuthorsMurray, J.M. / Wiesmann, C.
CitationJournal: To be Published
Title: Rational Design of PI3K-alpha Inhibitors that Exhibit Selectivity Over the PI3K-beta Isoform
Authors: Heffron, T. / Wei, B. / Olivero, A.G. / Staben, S.T. / Tsui, V. / Do, S. / Dotson, J. / Folkes, A. / Goldsmith, A. / Goldsmith, R. / Gunzner, J. / Lesnick, J. / Lewis, C. / Mathieu, S. / ...Authors: Heffron, T. / Wei, B. / Olivero, A.G. / Staben, S.T. / Tsui, V. / Do, S. / Dotson, J. / Folkes, A. / Goldsmith, A. / Goldsmith, R. / Gunzner, J. / Lesnick, J. / Lewis, C. / Mathieu, S. / Nonomiya, J. / Sutherlin, D.P. / Wan, N.C. / Wang, S. / Weismann, C. / Zhu, B.
History
DepositionAug 1, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 16, 2011Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.2Feb 28, 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)111,2802
Polymers110,7271
Non-polymers5531
Water27015
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)143.219, 67.651, 106.627
Angle α, β, γ (deg.)90.000, 95.550, 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 / 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: 110727.102 Da / Num. of mol.: 1 / Fragment: UNP residues 144-1102
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-3T8 / N~2~-{2-chloro-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-N~2~,N~8~-dimethyl-4,5-dihydrothieno[3,2-d][1]benzoxepine-2,8-dicarboxamide


Mass: 553.072 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H29ClN4O4S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 15 / 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: 2.32 Å3/Da / Density % sol: 47.02 %
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

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / 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
ReflectionRedundancy: 3.7 % / Number: 132569 / Rmerge(I) obs: 0.049 / Χ2: 1.08 / D res high: 2.5 Å / D res low: 50 Å / Num. obs: 35803 / % possible obs: 99.8
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squaredRedundancy
5.385098.510.0291.0413.5
4.275.3899.710.0451.0023.6
3.734.2799.810.0521.0313.6
3.393.7399.910.061.0593.7
3.153.3999.910.0811.1083.8
2.963.1510010.1271.1573.8
2.822.9610010.1911.143.8
2.692.8210010.2911.1473.8
2.592.6910010.4371.0533.8
2.52.5910010.6071.0233.8
ReflectionResolution: 2.5→50 Å / Num. all: 35803 / Num. obs: 35803 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Rmerge(I) obs: 0.465 / Net I/σ(I): 24
Reflection shellHighest resolution: 2.5 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.465 / Mean I/σ(I) obs: 24 / Num. unique all: 35803 / % possible all: 99.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXdev_833refinement
PDB_EXTRACT3.1data extraction
Blu-Icedata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→19.855 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.69 / σ(F): 1.34 / Phase error: 30.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2537 1744 4.94 %
Rwork0.2044 --
obs0.2069 35270 99.8 %
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 61.729 Å2 / ksol: 0.304 e/Å3
Displacement parametersBiso max: 261.69 Å2 / Biso mean: 106.0837 Å2 / Biso min: 36.1 Å2
Baniso -1Baniso -2Baniso -3
1-0.0723 Å20 Å21.9952 Å2
2--1.2612 Å2-0 Å2
3----1.3335 Å2
Refinement stepCycle: LAST / Resolution: 2.5→19.855 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6812 0 38 15 6865
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0137000
X-RAY DIFFRACTIONf_angle_d1.6879473
X-RAY DIFFRACTIONf_chiral_restr0.1081059
X-RAY DIFFRACTIONf_plane_restr0.0111202
X-RAY DIFFRACTIONf_dihedral_angle_d17.362601
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5001-2.57350.35831290.293227832912100
2.5735-2.65630.4061380.298527992937100
2.6563-2.75110.34451300.289627892919100
2.7511-2.86090.34731430.267927752918100
2.8609-2.99070.34311550.259527542909100
2.9907-3.14780.33971540.264328062960100
3.1478-3.34410.31311340.24627952929100
3.3441-3.60090.29961550.227127872942100
3.6009-3.96070.23021580.201727962954100
3.9607-4.52790.21261510.172827792930100
4.5279-5.68240.24911520.179428172969100
5.6824-19.85580.19481450.17572846299199
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)
14.6224-0.81120.54381.4004-0.58142.74620.1140.1376-1.0650.06480.16080.43540.02260.00540.03190.4923-0.03210.01240.1956-0.10190.633235.231237.202723.0263
23.2726-0.53450.58261.7936-0.10271.67650.0352-0.2437-0.38560.23770.1215-0.020.1830.45050.0010.56330.01930.01230.6753-0.04080.494155.789839.194635.4833
36.0394-1.80481.39852.4354-0.77392.3308-0.18250.0040.34690.43570.21380.2839-0.6609-0.4559-0.02270.64030.11330.09610.33930.09010.44325.975953.721425.9357
41.1012-0.02090.15810.3419-0.4370.4384-0.783-0.47672.2740.7260.0356-0.2801-1.58750.3389-0.17811.5891-0.0017-0.26120.6709-0.18531.473239.512467.938136.8394
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq 143:483)A0
2X-RAY DIFFRACTION2chain 'A' and (resseq 484:623)A0
3X-RAY DIFFRACTION3chain 'A' and (resseq 624:1038)A0
4X-RAY DIFFRACTION4chain 'A' and (resseq 1039:1091)A0

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