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- PDB-3zw3: Fragment based discovery of a novel and selective PI3 Kinase inhibitor -

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Basic information

Entry
Database: PDB / ID: 3zw3
TitleFragment based discovery of a novel and selective PI3 Kinase inhibitor
ComponentsPHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM
KeywordsTRANSFERASE
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-ZW3 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.8 Å
AuthorsBrown, D.G. / Hughes, S.J. / Milan, D.S. / Kilty, I.C. / Lewthwaite, R.A. / Mathias, J.P. / O'Reilly, M.A. / Pannifer, A. / Phelan, A. / Baldock, D.A.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2011
Title: Fragment based discovery of a novel and selective PI3 kinase inhibitor.
Authors: Hughes, S.J. / Millan, D.S. / Kilty, I.C. / Lewthwaite, R.A. / Mathias, J.P. / O'Reilly, M.A. / Pannifer, A. / Phelan, A. / Stuhmeier, F. / Baldock, D.A. / Brown, D.G.
History
DepositionJul 28, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 28, 2011Provider: repository / Type: Initial release
Revision 1.1Nov 16, 2011Group: Database references / Other
Revision 1.2Feb 7, 2018Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.journal_abbrev ..._audit_author.name / _citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)111,0292
Polymers110,7271
Non-polymers3021
Water2,306128
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.230, 68.520, 107.130
Angle α, β, γ (deg.)90.00, 95.64, 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 / PHOSPHOTIDYLINOSITOL 3 KINASE / PI3-KINASE SUBUNIT GAMMA / PI3K-GAMMA / PTDINS-3-KINASE SUBUNIT ...PHOSPHOTIDYLINOSITOL 3 KINASE / 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 / PI3 KINASE GAMMA


Mass: 110727.102 Da / Num. of mol.: 1 / Fragment: RESIDUES 144-1102 / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-ZW3 / N-{6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]imidazo[1,2-a]pyridin-2-yl}acetamide


Mass: 302.309 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H10N4O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 128 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsGLN-ARG AT 459 IS ANNOTATED AS A CONFLICT IN UNIPROT

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.35 Å3/Da / Density % sol: 47.55 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.98
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 1, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.8→106.6 Å / Num. obs: 25431 / % possible obs: 99.5 % / Observed criterion σ(I): 2 / Redundancy: 3.4 % / Biso Wilson estimate: 84.24 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 14.3

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Processing

Software
NameVersionClassification
BUSTER2.9.6refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2.8→18.28 Å / Cor.coef. Fo:Fc: 0.9351 / Cor.coef. Fo:Fc free: 0.9199 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.299
RfactorNum. reflection% reflectionSelection details
Rfree0.2109 1290 5.09 %RANDOM
Rwork0.1857 ---
obs0.1871 25330 99.5 %-
Displacement parametersBiso mean: 92.34 Å2
Baniso -1Baniso -2Baniso -3
1--10.509 Å20 Å2-8.4308 Å2
2--0.1519 Å20 Å2
3---10.357 Å2
Refine analyzeLuzzati coordinate error obs: 0.475 Å
Refinement stepCycle: LAST / Resolution: 2.8→18.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6722 0 21 128 6871
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016887HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.099314HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2431SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes185HARMONIC2
X-RAY DIFFRACTIONt_gen_planes973HARMONIC5
X-RAY DIFFRACTIONt_it6887HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.4
X-RAY DIFFRACTIONt_other_torsion19.6
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion893SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7622SEMIHARMONIC4
LS refinement shellResolution: 2.8→2.91 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2679 144 5.04 %
Rwork0.2232 2714 -
all0.2254 2858 -
obs--99.5 %
Refinement TLS params.Method: refined / Origin x: 32.4696 Å / Origin y: -0.0822 Å / Origin z: 25.9346 Å
111213212223313233
T-0.0964 Å20.0685 Å20.1162 Å2--0.372 Å20.0195 Å2---0.3087 Å2
L3.6826 °21.2046 °20.8705 °2-1.8155 °20.244 °2--2.4609 °2
S-0.2299 Å °-0.2123 Å °-0.3447 Å °-0.5352 Å °0.1777 Å °-0.3953 Å °-0.3632 Å °-0.044 Å °0.0523 Å °
Refinement TLS groupSelection details: (CHAIN A AND RESID 144:1090)

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