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Basic information

Entry
Database: PDB / ID: 3zim
TitleDiscovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kalpha
ComponentsPHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT ALPHA ISOFORM
KeywordsTRANSFERASE
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K ...response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IB / vasculature development / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / phosphatidylinositol 3-kinase complex, class IA / anoikis / phosphatidylinositol 3-kinase complex / Nephrin family interactions / Costimulation by the CD28 family / relaxation of cardiac muscle / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / MET activates PI3K/AKT signaling / PI3K/AKT activation / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / negative regulation of macroautophagy / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR2 / response to dexamethasone / PI-3K cascade:FGFR4 / protein kinase activator activity / PI-3K cascade:FGFR1 / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / PI3K events in ERBB2 signaling / negative regulation of anoikis / RET signaling / intercalated disc / regulation of multicellular organism growth / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / Role of phospholipids in phagocytosis / GAB1 signalosome / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / adipose tissue development / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / phagocytosis / positive regulation of lamellipodium assembly / energy homeostasis / Signaling by FGFR4 in disease / cardiac muscle contraction / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR3 in disease / Tie2 Signaling / GPVI-mediated activation cascade / Signaling by FGFR2 in disease / T cell costimulation / RAC1 GTPase cycle / response to muscle stretch / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Downstream signal transduction / phosphatidylinositol 3-kinase/protein kinase B signal transduction / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / liver development / response to activity / Regulation of signaling by CBL / cellular response to glucose stimulus / positive regulation of smooth muscle cell proliferation / regulation of protein phosphorylation / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / Signaling by SCF-KIT / platelet activation / VEGFA-VEGFR2 Pathway / cellular response to insulin stimulus / Constitutive Signaling by Aberrant PI3K in Cancer / glucose metabolic process
Similarity search - Function
PI3Kalpha, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain ...PI3Kalpha, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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-KKR / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsNacht, M. / Qiao, L. / Sheets, M.P. / Martin, T.S. / Labenski, M. / Mazdiyasni, H. / Karp, R. / Zhu, Z. / Chaturvedi, P. / Bhavsar, D. ...Nacht, M. / Qiao, L. / Sheets, M.P. / Martin, T.S. / Labenski, M. / Mazdiyasni, H. / Karp, R. / Zhu, Z. / Chaturvedi, P. / Bhavsar, D. / Niu, D. / Westlin, W. / Petter, R.C. / Medikonda, A.P. / Jestel, A. / Blaesse, M. / Singh, J.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of a Potent and Isoform-Selective Targeted Covalent Inhibitor of the Lipid Kinase Pi3Kalpha
Authors: Nacht, M. / Qiao, L. / Sheets, M.P. / Martin, T.S. / Labenski, M. / Mazdiyasni, H. / Karp, R. / Zhu, Z. / Chaturvedi, P. / Bhavsar, D. / Niu, D. / Westlin, W. / Petter, R.C. / Medikonda, A.P. / Singh, J.
History
DepositionJan 9, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 13, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2013Group: Database references
Revision 1.2May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_database_status / pdbx_entity_nonpoly / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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 ALPHA ISOFORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,9802
Polymers109,4061
Non-polymers5741
Water1267
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)59.340, 135.027, 142.921
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT ALPHA ISOFORM / PI3-KINASE SUBUNIT ALPHA / PI3K-ALPHA / PI3KALPHA / PTDINS-3-KINASE SUBUNIT ALPHA / ...PI3-KINASE SUBUNIT ALPHA / PI3K-ALPHA / PI3KALPHA / PTDINS-3-KINASE SUBUNIT ALPHA / PHOSPHATIDYLINOSITOL 4 / 5-BISPHOSPHATE 3-KINASE 110 KDA CATALYTIC SUBUNIT ALPHA / PTDINS-3-KINASE SUBUNIT P110-ALPHA / P110ALPHA / PHOSPHOINOSITIDE-3-KINASE CATALYTIC ALPHA POLYPEPTIDE / SERINE/THREONINE PROTEIN KINASE PIK3CA


Mass: 109406.477 Da / Num. of mol.: 1 / Fragment: N-TERMINAL TRUNCATED, RESIDUES 107-1046
Source method: isolated from a genetically manipulated source
Details: LIGAND COVALENTLY LINKED TO CYS862 / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-KKR / 1-[4-[[2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-6-methyl-hept-5-ene-1,4- dione / 1-[4-[[2-(1H-indazol-4-yl)-4-morpholinthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-6-methyl-hept-5-ene-1,4-dione


Mass: 573.709 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H35N7O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / 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: 2.71 Å3/Da / Density % sol: 54.59 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00002
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 22, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 2.85→98.15 Å / Num. obs: 27581 / % possible obs: 99.8 % / Redundancy: 5.9 % / Biso Wilson estimate: 97.901 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 14.3
Reflection shellResolution: 2.85→3.04 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.43 / Mean I/σ(I) obs: 1.8 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
XDSdata reduction
SCALAdata scaling
REFMACRIGID BODYphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PREVIOUSLY SOLVED STRUCTURE

Resolution: 2.85→98.15 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.902 / Cross valid method: THROUGHOUT / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED. DISORDERED SIDE CHAINS WERE MODELED STEREOCHEMICALLY.
RfactorNum. reflection% reflectionSelection details
Rfree0.27822 719 2.6 %RANDOM
Rwork0.21272 ---
obs0.21434 26820 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 105.053 Å2
Baniso -1Baniso -2Baniso -3
1--0.35 Å20 Å20 Å2
2--0.52 Å20 Å2
3----0.17 Å2
Refinement stepCycle: LAST / Resolution: 2.85→98.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7238 0 41 7 7286
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.026844
X-RAY DIFFRACTIONr_bond_other_d0.0010.024699
X-RAY DIFFRACTIONr_angle_refined_deg1.1181.9599337
X-RAY DIFFRACTIONr_angle_other_deg0.989311148
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6965879
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.42424.342281
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.273151005
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8741528
X-RAY DIFFRACTIONr_chiral_restr0.0620.21057
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0217765
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021395
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.85→2.924 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.429 55 -
Rwork0.337 1751 -
obs--99.89 %
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)
16.37090.6064-0.36272.38490.28283.18850.1302-0.1319-0.01350.26610.06850.52260.1524-0.8669-0.19880.1043-0.06610.03480.99530.02380.086-11.9123.57240.643
23.9709-0.3716-0.71692.4726-0.93894.00880.15870.79210.491-0.42980.00190.4377-0.5916-1.0702-0.16070.31250.0819-0.03671.11960.1280.3134-12.22817.87415.558
31.2348-1.2726-0.41665.92151.70072.1475-0.0352-0.05220.3940.51360.1847-0.4039-0.21010.1461-0.14960.1652-0.11570.05360.81860.0380.293111.0416.43438.265
43.21252.4399-1.60713.6977-2.25844.1171-0.29370.7952-0.6813-0.44270.0408-0.12420.86620.05720.25290.52350.04410.12310.875-0.2580.294413.272-17.9023.815
51.69040.0047-0.95160.80190.36585.37160.1180.4050.2138-0.4398-0.0153-0.1653-0.36870.2225-0.10280.1832-0.04230.09320.90050.04840.107314.1454.0759.798
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A696 - 804
2X-RAY DIFFRACTION1A2047
3X-RAY DIFFRACTION2A805 - 1111
4X-RAY DIFFRACTION3A100 - 305
5X-RAY DIFFRACTION4A306 - 510
6X-RAY DIFFRACTION5A511 - 695

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