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- PDB-4flh: Crystal structure of human PI3K-gamma in complex with AMG511 -

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Basic information

Entry
Database: PDB / ID: 4flh
TitleCrystal structure of human PI3K-gamma in complex with AMG511
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTransferase/Inhibitor / p110 / phosphotransferase / cancer / p85 / phosphorylation / 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-14K / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.6 Å
AuthorsWhittington, D.A. / Tang, J. / Yakowec, P.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511.
Authors: Norman, M.H. / Andrews, K.L. / Bo, Y.Y. / Booker, S.K. / Caenepeel, S. / Cee, V.J. / D'Angelo, N.D. / Freeman, D.J. / Herberich, B.J. / Hong, F.T. / Jackson, C.L. / Jiang, J. / Lanman, B.A. ...Authors: Norman, M.H. / Andrews, K.L. / Bo, Y.Y. / Booker, S.K. / Caenepeel, S. / Cee, V.J. / D'Angelo, N.D. / Freeman, D.J. / Herberich, B.J. / Hong, F.T. / Jackson, C.L. / Jiang, J. / Lanman, B.A. / Liu, L. / McCarter, J.D. / Mullady, E.L. / Nishimura, N. / Pettus, L.H. / Reed, A.B. / Miguel, T.S. / Smith, A.L. / Stec, M.M. / Tadesse, S. / Tasker, A. / Aidasani, D. / Zhu, X. / Subramanian, R. / Tamayo, N.A. / Wang, L. / Whittington, D.A. / Wu, B. / Wu, T. / Wurz, R.P. / Yang, K. / Zalameda, L. / Zhang, N. / Hughes, P.E.
History
DepositionJun 14, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 29, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 3, 2012Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Feb 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)110,7266
Polymers109,8241
Non-polymers9025
Water75742
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)145.059, 67.803, 107.523
Angle α, β, γ (deg.)90.000, 95.270, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1341-

HOH

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform / PI3-kinase subunit gamma / PI3K-gamma / PI3Kgamma / PtdIns-3-kinase subunit gamma / ...PI3-kinase subunit gamma / PI3K-gamma / PI3Kgamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 109824.055 Da / Num. of mol.: 1 / Fragment: catalytic domain, 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, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-14K / 4-(2-[(5-fluoro-6-methoxypyridin-3-yl)amino]-5-{(1R)-1-[4-(methylsulfonyl)piperazin-1-yl]ethyl}pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine


Mass: 517.580 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H28FN9O3S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 42 / 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: 2.4 Å3/Da / Density % sol: 48.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 21% PEG 3350, 200 mM ammonium sulfate, 2 mM DTT, 100 mM Tris, pH 7.3, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jun 13, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.59→50 Å / Num. all: 32605 / Num. obs: 32540 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 3.8 % / Biso Wilson estimate: 73.9 Å2 / Rmerge(I) obs: 0.052 / Χ2: 1.029 / Net I/σ(I): 16.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.59-2.683.80.56132271.0441100
2.68-2.793.80.39132171.0551100
2.79-2.923.80.26832411.0191100
2.92-3.073.80.17932641.0641100
3.07-3.263.80.13332121.011100
3.26-3.513.80.0932461.003199.9
3.51-3.873.80.0632491.036199.8
3.87-4.433.80.04432761.035199.9
4.43-5.583.60.04232781.009199.8
5.58-503.60.02733301.015199

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.6→41.15 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.941 / WRfactor Rfree: 0.2721 / WRfactor Rwork: 0.2147 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8108 / SU B: 25.633 / SU ML: 0.255 / SU R Cruickshank DPI: 0.8047 / SU Rfree: 0.3072 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.805 / ESU R Free: 0.307 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2443 1635 5.1 %RANDOM
Rwork0.1997 ---
obs0.202 32236 99.78 %-
all-32307 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 174.67 Å2 / Biso mean: 77.6399 Å2 / Biso min: 35.38 Å2
Baniso -1Baniso -2Baniso -3
1--1.38 Å20 Å20.54 Å2
2--1.93 Å20 Å2
3----0.45 Å2
Refinement stepCycle: LAST / Resolution: 2.6→41.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6807 0 56 42 6905
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.027007
X-RAY DIFFRACTIONr_bond_other_d0.0010.024779
X-RAY DIFFRACTIONr_angle_refined_deg1.081.9689485
X-RAY DIFFRACTIONr_angle_other_deg0.814311650
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6765830
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.39224.338325
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.314151266
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9791540
X-RAY DIFFRACTIONr_chiral_restr0.0640.21072
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0217571
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021396
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.336 109 -
Rwork0.288 2146 -
all-2255 -
obs--99.82 %
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)
13.6025-0.85970.67240.6972-0.41381.74180.2463-0.0849-1.2647-0.06120.1710.54480.1344-0.2242-0.41730.1383-0.0249-0.00890.12510.11190.625521.7804-14.201528.1223
22.4496-1.85281.90472.7118-0.37082.6420.0766-0.9135-1.1696-0.15590.81810.8561-0.3196-0.8428-0.89480.16520.06130.11580.47840.41440.76913.0139-12.397531.5952
31.0919-0.1037-0.35962.3112-1.3272.55350.06530.4233-0.00840.06130.0526-0.0788-0.06380.5308-0.11790.15760.02280.0360.7061-0.10670.175967.3318-5.58814.9866
41.64260.46250.14450.88870.37370.2205-0.10180.9284-0.15930.15920.166-0.00560.04710.1887-0.06430.27480.03240.06270.9119-0.15920.177457.2921-8.533714.1221
52.9922-0.29931.46690.2786-0.20681.15750.0860.0215-0.4330.0510.05970.1151-0.0010.1053-0.14560.29740.0480.01610.25270.00080.325246.4652-10.031134.415
62.0293-0.96280.9331.1047-0.5970.71350.03210.3118-0.12950.06140.08330.215-0.2107-0.045-0.11540.30.07040.03710.3760.04960.26520.69925.364617.5422
72.0386-0.66390.91081.5229-0.85780.7673-0.6732-0.24280.48250.64470.3124-0.2123-0.4591-0.10670.36090.66660.2168-0.12730.2503-0.06930.294130.009719.786837.6364
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A145 - 249
2X-RAY DIFFRACTION2A269 - 321
3X-RAY DIFFRACTION3A352 - 436
4X-RAY DIFFRACTION4A457 - 533
5X-RAY DIFFRACTION5A546 - 725
6X-RAY DIFFRACTION6A726 - 885
7X-RAY DIFFRACTION7A886 - 1092

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