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- PDB-4ykn: Pi3K alpha lipid kinase with Active Site Inhibitor -

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Basic information

Entry
Database: PDB / ID: 4ykn
TitlePi3K alpha lipid kinase with Active Site Inhibitor
ComponentsPhosphatidylinositol 3-kinase regulatory subunit alpha,Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform fusion protein
KeywordsTransferase/Transferase Inhibitor / "Lipid Kinase" / inhibitor / complex / Pi3K / Pi3K alpha / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / phosphatidylinositol 3-kinase regulator activity / response to butyrate / positive regulation of focal adhesion disassembly ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / phosphatidylinositol 3-kinase regulator activity / response to butyrate / positive regulation of focal adhesion disassembly / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulatory subunit binding / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / cis-Golgi network / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / cardiac muscle cell contraction / RHOF GTPase cycle / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex, class IA / anoikis / phosphatidylinositol 3-kinase complex / Nephrin family interactions / RND1 GTPase cycle / Costimulation by the CD28 family / relaxation of cardiac muscle / positive regulation of leukocyte migration / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / MET activates PI3K/AKT signaling / RND2 GTPase cycle / PI3K/AKT activation / positive regulation of filopodium assembly / RND3 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / negative regulation of stress fiber assembly / growth hormone receptor signaling pathway / phosphatidylinositol 3-kinase / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / RHOV GTPase cycle / 1-phosphatidylinositol-3-kinase activity / negative regulation of cell-matrix adhesion / Signaling by ALK / RHOB GTPase cycle / negative regulation of macroautophagy / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR2 / response to dexamethasone / RHOJ GTPase cycle / PI-3K cascade:FGFR4 / protein kinase activator activity / RHOC GTPase cycle / PI-3K cascade:FGFR1 / negative regulation of osteoclast differentiation / intracellular glucose homeostasis / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / T cell differentiation / RET signaling / intercalated disc / regulation of multicellular organism growth / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / RHOG GTPase cycle / extrinsic apoptotic signaling pathway via death domain receptors / PI3K Cascade / RHOA GTPase cycle / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / RAC3 GTPase cycle / Role of phospholipids in phagocytosis
Similarity search - Function
Helix Hairpins - #1490 / PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) ...Helix Hairpins - #1490 / PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 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 / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / 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) / Rho GTPase activation protein / 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 / SH2 domain / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / Ubiquitin-like (UB roll) / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Alpha Horseshoe / Helix Hairpins / 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-4EL / Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsElkins, P.A.
Citation
Journal: Acs Med.Chem.Lett. / Year: 2015
Title: Discovery of a Potent Class of PI3K alpha Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT).
Authors: Yang, H. / Medeiros, P.F. / Raha, K. / Elkins, P. / Lind, K.E. / Lehr, R. / Adams, N.D. / Burgess, J.L. / Schmidt, S.J. / Knight, S.D. / Auger, K.R. / Schaber, M.D. / Franklin, G.J. / Ding, ...Authors: Yang, H. / Medeiros, P.F. / Raha, K. / Elkins, P. / Lind, K.E. / Lehr, R. / Adams, N.D. / Burgess, J.L. / Schmidt, S.J. / Knight, S.D. / Auger, K.R. / Schaber, M.D. / Franklin, G.J. / Ding, Y. / DeLorey, J.L. / Centrella, P.A. / Mataruse, S. / Skinner, S.R. / Clark, M.A. / Cuozzo, J.W. / Evindar, G.
#1: Journal: PROTEIN EXPR.PURIF. / Year: 2010
Title: Baculovirus production of fully-active phosphoinositide 3-kinase alpha as a p85a-p110a fusion for X-ray crystallographic analysis with ATP competitive enzyme inhibitors
Authors: Sinnamon, R.H. / McDevitt, P. / Pietrak, B.L. / Leydon, V.R. / Xue, Y. / Lehr, R. / Qi, H. / Burns, M. / Elkins, P. / Ward, P. / Vincentini, G. / Fisher, D. / Grimes, M. / Brandt, M. / ...Authors: Sinnamon, R.H. / McDevitt, P. / Pietrak, B.L. / Leydon, V.R. / Xue, Y. / Lehr, R. / Qi, H. / Burns, M. / Elkins, P. / Ward, P. / Vincentini, G. / Fisher, D. / Grimes, M. / Brandt, M. / Auger, K.R. / Ho, T. / Johanson, K. / Jones, C.S. / Schwartz, B. / Sweitzer, T.D. / Kirkpatrick, R.B.
History
DepositionMar 4, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_oper_list / software
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phosphatidylinositol 3-kinase regulatory subunit alpha,Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform fusion protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)163,3804
Polymers161,8451
Non-polymers1,5353
Water1,69394
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area52690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.667, 118.191, 190.281
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 3-kinase regulatory subunit alpha,Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform fusion protein / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit ...PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PtdIns-3-kinase regulatory subunit p85-alpha / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / p110alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 161845.297 Da / Num. of mol.: 1
Fragment: UNP P27986 residues 318-615, LINKER (GSPGISGGGGG), P42336 residues 2-1068
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1, PIK3CA / Production host: unidentified baculovirus
References: UniProt: P27986, UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-4EL / 3-(6-methoxypyridin-3-yl)-5-[({4-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfamoyl]phenyl}amino)methyl]benzoic acid


Mass: 511.573 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C23H21N5O5S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 2.94 Å3/Da / Density % sol: 58.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: ethylenene glycol, PIP2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 6, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 43067 / % possible obs: 100 % / Redundancy: 7.4 % / Biso Wilson estimate: 51.84 Å2 / Rmerge(I) obs: 0.121 / Χ2: 1.057 / Net I/av σ(I): 17.105 / Net I/σ(I): 7.7 / Num. measured all: 319029
Reflection shell

Diffraction-ID: 1 / Rejects: _ / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2
2.9-37.60.54942011.052
3-3.127.60.42642311.094
3.12-3.277.60.31442261.049
3.27-3.447.50.22942241.074
3.44-3.657.50.16642381.011
3.65-3.947.50.11942611.009
3.94-4.337.50.10342601.064
4.33-4.967.40.09643141.053
4.96-6.247.40.08143291.093
6.24-506.90.0545541.076

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: dev_1801)refinement
HKL-2000data scaling
PHASERphasing
SCALAdata scaling
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→29.93 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.19 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2472 2182 5.07 %
Rwork0.2015 --
obs0.2038 43058 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.9→29.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9464 0 105 94 9663
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0039797
X-RAY DIFFRACTIONf_angle_d0.54713298
X-RAY DIFFRACTIONf_dihedral_angle_d13.4913546
X-RAY DIFFRACTIONf_chiral_restr0.0341477
X-RAY DIFFRACTIONf_plane_restr0.0031701
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-2.9630.32321360.26152519X-RAY DIFFRACTION100
2.963-3.03190.32151330.24822546X-RAY DIFFRACTION100
3.0319-3.10760.2851310.24112495X-RAY DIFFRACTION100
3.1076-3.19150.25071290.22492526X-RAY DIFFRACTION100
3.1915-3.28530.30741290.22912532X-RAY DIFFRACTION100
3.2853-3.39120.27781330.242525X-RAY DIFFRACTION100
3.3912-3.51230.26561500.22222510X-RAY DIFFRACTION100
3.5123-3.65270.26531300.21572536X-RAY DIFFRACTION100
3.6527-3.81860.24911410.19072538X-RAY DIFFRACTION100
3.8186-4.01950.22331240.18122544X-RAY DIFFRACTION100
4.0195-4.27060.20921260.17742571X-RAY DIFFRACTION100
4.2706-4.59930.20211420.1622538X-RAY DIFFRACTION100
4.5993-5.06010.19381520.15542563X-RAY DIFFRACTION100
5.0601-5.78770.22021310.18822596X-RAY DIFFRACTION100
5.7877-7.27460.28521440.22572613X-RAY DIFFRACTION100
7.2746-29.93150.2631510.20832724X-RAY DIFFRACTION100
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)
16.6986-1.29873.09232.3022-0.66884.9696-0.1670.40760.9422-0.1530.17790.4853-0.74570.14460.01750.48030.01-0.07880.36510.13660.7736-41.826927.6388-23.1856
23.6674-2.0532.79792.1751-1.59652.5594-0.10720.34290.50140.0357-0.1504-0.0723-0.12560.25190.2560.3301-0.07520.02050.2390.03190.367310.819314.7117-1.1557
36.44420.3661.72770.52120.25561.2505-0.01980.0957-0.09390.09940.0929-0.1080.20460.1042-0.05830.30180.01440.01690.1396-0.00140.227611.0099-8.00810.8677
40.4885-0.5415-0.20061.77740.87990.9315-0.01430.06240.0961-0.11450.0309-0.05060.0223-0.0441-0.05370.2208-0.05930.02350.2156-0.02310.2994-16.683-4.8223-16.9712
52.6398-0.429-0.59710.65340.05491.1784-0.08510.13480.02690.02520.0130.02850.0041-0.0140.03890.2335-0.08670.01410.1542-0.03730.1877-18.5797-1.2326-17.153
61.3668-0.0471-0.46450.6217-0.43512.19060.0430.37910.1215-0.248-0.0010.06120.0754-0.2884-0.04840.3194-0.04410.00790.33770.03380.2112-14.22932.7722-43.0832
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 331:428 )A331 - 428
2X-RAY DIFFRACTION2( CHAIN A AND RESID 452:580 )A452 - 580
3X-RAY DIFFRACTION3( CHAIN A AND RESID 1010:1154 )A1010 - 1154
4X-RAY DIFFRACTION4( CHAIN A AND RESID 1155:1477 )A1155 - 1477
5X-RAY DIFFRACTION5( CHAIN A AND RESID 1478:1784 )A1478 - 1784
6X-RAY DIFFRACTION6( CHAIN A AND RESID 1785:2052 )A1785 - 2052

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