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- PDB-5is5: Discovery and Pharmacological Characterization of Novel Quinazoli... -

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Basic information

Entry
Database: PDB / ID: 5is5
TitleDiscovery and Pharmacological Characterization of Novel Quinazoline-based PI3K delta-selective Inhibitors
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / Phosphoinositide 3-Kinase / isoform-sepcific inhibitors
Function / homology
Function and homology information


positive regulation of multicellular organismal process / regulation of multicellular organismal development / regulation of anatomical structure morphogenesis / positive regulation of developmental process / Co-stimulation by ICOS / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / CD28 dependent PI3K/Akt signaling / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling ...positive regulation of multicellular organismal process / regulation of multicellular organismal development / regulation of anatomical structure morphogenesis / positive regulation of developmental process / Co-stimulation by ICOS / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / CD28 dependent PI3K/Akt signaling / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / B cell activation / B cell homeostasis / homeostasis of number of cells / defense response to fungus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of angiogenesis / chemotaxis / adaptive immune response / cell differentiation / cell surface receptor signaling pathway / inflammatory response / innate immune response / positive regulation of gene expression / ATP binding / cytosol
Similarity search - Function
PI3Kdelta, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. ...PI3Kdelta, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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 / C2 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-6CY / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsGutmann, S. / Rummel, G. / Shrestha, B.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.
Authors: Hoegenauer, K. / Soldermann, N. / Stauffer, F. / Furet, P. / Graveleau, N. / Smith, A.B. / Hebach, C. / Hollingworth, G.J. / Lewis, I. / Gutmann, S. / Rummel, G. / Knapp, M. / Wolf, R.M. / ...Authors: Hoegenauer, K. / Soldermann, N. / Stauffer, F. / Furet, P. / Graveleau, N. / Smith, A.B. / Hebach, C. / Hollingworth, G.J. / Lewis, I. / Gutmann, S. / Rummel, G. / Knapp, M. / Wolf, R.M. / Blanz, J. / Feifel, R. / Burkhart, C. / Zecri, F.
History
DepositionMar 15, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 10, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 14, 2016Group: Database references
Revision 1.2Jan 18, 2017Group: Data collection
Revision 1.3Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.4Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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 delta isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,4922
Polymers119,9991
Non-polymers4931
Water4,179232
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area33900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.460, 64.320, 116.640
Angle α, β, γ (deg.)90.00, 103.20, 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 delta isoform


Mass: 119999.461 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Pik3cd / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q3UDT3, UniProt: O35904*PLUS, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-6CY / 5-{4-[3-(4-acetylpiperazine-1-carbonyl)phenyl]quinazolin-6-yl}-2-methoxypyridine-3-carbonitrile


Mass: 492.529 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H24N6O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / 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: 2.15 Å3/Da / Density % sol: 42.86 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop
Details: 13 mM NaNO4, 13 mM ammonium sulfate, 13 mM Na2HPO4, 16.4 (v/v) % glycerol, 13 % (w/v) PEG4000, 0.1M imidazole pH6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 11, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.85→68.87 Å / Num. obs: 23618 / % possible obs: 97.7 % / Redundancy: 3.29 % / Rmerge(I) obs: 0.2294 / Rsym value: 0.101 / Net I/σ(I): 11.74
Reflection shellResolution: 2.61→2.68 Å

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Processing

Software
NameClassification
BUSTER-TNTrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2xwf

2xwf
PDB Unreleased entry


Resolution: 2.85→65.95 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.2709 --
Rwork0.2294 --
obs-23616 97.8 %
Refinement stepCycle: LAST / Resolution: 2.85→65.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5648 0 37 232 5917

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