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- PDB-4xx5: Structure of PI3K gamma in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4xx5
TitleStructure of PI3K gamma in complex with an inhibitor
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / Inhibitor / 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 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / mast cell degranulation / 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-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / phosphorylation / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / ephrin receptor binding / neutrophil chemotaxis / 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-43R / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.76 Å
AuthorsCollier, P.N. / Messersmith, D. / Le Tiran, A. / Bandarage, U.K. / Boucher, C. / Come, J. / Cottrell, K.M. / Damagnez, V. / Doran, J.D. / Griffith, J.P. ...Collier, P.N. / Messersmith, D. / Le Tiran, A. / Bandarage, U.K. / Boucher, C. / Come, J. / Cottrell, K.M. / Damagnez, V. / Doran, J.D. / Griffith, J.P. / Khare-Pandit, S. / Krueger, E.B. / Ledeboer, M.W. / Ledford, B. / Liao, Y. / Mahajan, S. / Moody, C.S. / Wang, T. / Xu, J. / Aronov, A.M.
CitationJournal: To Be Published
Title: Structure of PI3K gamma in complex with an inhibitor
Authors: Collier, P.N. / Messersmith, D. / Le Tiran, A. / Bandarage, U.K. / Boucher, C. / Come, J. / Cottrell, K.M. / Damagnez, V. / Doran, J.D. / Griffith, J.P. / Khare-Pandit, S. / Krueger, E.B. / ...Authors: Collier, P.N. / Messersmith, D. / Le Tiran, A. / Bandarage, U.K. / Boucher, C. / Come, J. / Cottrell, K.M. / Damagnez, V. / Doran, J.D. / Griffith, J.P. / Khare-Pandit, S. / Krueger, E.B. / Ledeboer, M.W. / Ledford, B. / Liao, Y. / Mahajan, S. / Moody, C.S. / Wang, T. / Xu, J. / Aronov, A.M.
History
DepositionJan 29, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 5, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)111,0612
Polymers110,7561
Non-polymers3041
Water905
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.444, 67.418, 106.698
Angle α, β, γ (deg.)90.00, 95.67, 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 / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 110756.164 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 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-43R / N-[5-(5-methoxypyridin-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]acetamide


Mass: 304.367 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H16N4O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 2.33 Å3/Da / Density % sol: 47.3 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 25% PEG3350, 200 MM LITHIUM SULFATE,10 MM DTT, 10 MM EDTA, 100 MM TRIS

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 18, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.76→106.18 Å / Num. obs: 18263 / % possible obs: 72.49 % / Redundancy: 3.2 % / Net I/σ(I): 5.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.76→106.18 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.9 / Occupancy max: 1 / Occupancy min: 1 / SU B: 49.757 / SU ML: 0.407 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.526 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2742 959 5 %RANDOM
Rwork0.1981 17304 --
obs0.202 18263 72.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 159.89 Å2 / Biso mean: 58.3277 Å2 / Biso min: 23.58 Å2
Baniso -1Baniso -2Baniso -3
1--1.09 Å20 Å24.1 Å2
2--3.83 Å20 Å2
3----3.49 Å2
Refinement stepCycle: LAST / Resolution: 2.76→106.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6844 0 21 5 6870
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0197015
X-RAY DIFFRACTIONr_bond_other_d0.0010.026791
X-RAY DIFFRACTIONr_angle_refined_deg1.4761.9629489
X-RAY DIFFRACTIONr_angle_other_deg0.819315618
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4735835
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.82124.212330
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.944151275
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8811543
X-RAY DIFFRACTIONr_chiral_restr0.0750.21062
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0217775
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021615
X-RAY DIFFRACTIONr_mcbond_it3.4065.5533363
X-RAY DIFFRACTIONr_mcbond_other3.4055.5533362
X-RAY DIFFRACTIONr_mcangle_it5.8298.3094190
LS refinement shellResolution: 2.761→2.833 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.587 1 -
Rwork0.333 39 -
all-40 -
obs--2.05 %
Refinement TLS params.Method: refined / Origin x: 34.7002 Å / Origin y: 47.2864 Å / Origin z: 27.0088 Å
111213212223313233
T0.2663 Å20.0281 Å2-0.0021 Å2-0.0382 Å20.0226 Å2--0.1461 Å2
L4.0688 °2-0.6632 °21.0879 °2-1.4943 °2-0.2957 °2--2.4279 °2
S-0.0476 Å °0.1779 Å °-0.1427 Å °0.1606 Å °0.1377 Å °0.2304 Å °-0.2999 Å °-0.0367 Å °-0.0901 Å °

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