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- PDB-5vlr: CRYSTAL STRUCTURE OF PI3K DELTA IN COMPLEX WITH A TRIFLUORO-ETHYL... -

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Entry
Database: PDB / ID: 5vlr
TitleCRYSTAL STRUCTURE OF PI3K DELTA IN COMPLEX WITH A TRIFLUORO-ETHYL-PYRAZOL-PYROLOTRIAZINE INHIBITOR
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE/TRANSFERASE REGULATOR / LIPID KINASE / INHIBITOR / PI3K DELTA / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX / TRANSFERASE-TRANSFERASE REGULATOR complex
Function / homology
Function and homology information


B cell chemotaxis / mast cell differentiation / mast cell chemotaxis / natural killer cell differentiation / perinuclear endoplasmic reticulum membrane / natural killer cell chemotaxis / regulation of toll-like receptor 4 signaling pathway / neutrophil extravasation / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / phosphatidylinositol kinase activity ...B cell chemotaxis / mast cell differentiation / mast cell chemotaxis / natural killer cell differentiation / perinuclear endoplasmic reticulum membrane / natural killer cell chemotaxis / regulation of toll-like receptor 4 signaling pathway / neutrophil extravasation / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / phosphatidylinositol kinase activity / phosphatidylinositol 3-kinase regulator activity / respiratory burst involved in defense response / positive regulation of focal adhesion disassembly / IRS-mediated signalling / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / positive regulation of epithelial tube formation / PI3K events in ERBB4 signaling / myeloid leukocyte migration / phosphatidylinositol 3-kinase regulatory subunit binding / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of neutrophil apoptotic process / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / T cell chemotaxis / natural killer cell activation / cis-Golgi network / Activated NTRK3 signals through PI3K / kinase activator activity / ErbB-3 class receptor binding / RHOF GTPase cycle / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / positive regulation of endoplasmic reticulum unfolded protein response / Signaling by cytosolic FGFR1 fusion mutants / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex / Nephrin family interactions / 1-phosphatidylinositol-4-phosphate 3-kinase activity / RND1 GTPase cycle / Costimulation by the CD28 family / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / RND2 GTPase cycle / PI3K/AKT activation / MET activates PI3K/AKT signaling / RND3 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of leukocyte migration / positive regulation of filopodium assembly / phosphatidylinositol 3-kinase / phosphatidylinositol 3-kinase complex, class IA / negative regulation of stress fiber assembly / growth hormone receptor signaling pathway / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / RHOV GTPase cycle / GP1b-IX-V activation signalling / RHOB GTPase cycle / Signaling by ALK / mast cell degranulation / negative regulation of cell-matrix adhesion / B cell activation / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR2 / RHOJ GTPase cycle / PI-3K cascade:FGFR4 / 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 phosphate biosynthetic process / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / Signaling by ALK fusions and activated point mutants / RHOG GTPase cycle / RET signaling / T cell differentiation / extrinsic apoptotic signaling pathway via death domain receptors / insulin receptor substrate binding / PI3K Cascade / Interleukin-3, Interleukin-5 and GM-CSF signaling / RHOA GTPase cycle / RAC3 GTPase cycle / RAC2 GTPase cycle / Role of phospholipids in phagocytosis / GAB1 signalosome / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / positive regulation of lamellipodium assembly / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Signaling by FGFR4 in disease / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR3 in disease
Similarity search - Function
PI3Kdelta, 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain ...PI3Kdelta, 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 / 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 / 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 / C2 domain superfamily / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / Src homology 3 domains / SH2 domain / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-9EM / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / Phosphatidylinositol 3-kinase regulatory subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSack, J.S.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase delta (PI3K delta ) Inhibitor for the Treatment of Immunological Disorders.
Authors: Liu, Q. / Shi, Q. / Marcoux, D. / Batt, D.G. / Cornelius, L. / Qin, L.Y. / Ruan, Z. / Neels, J. / Beaudoin-Bertrand, M. / Srivastava, A.S. / Li, L. / Cherney, R.J. / Gong, H. / Watterson, S. ...Authors: Liu, Q. / Shi, Q. / Marcoux, D. / Batt, D.G. / Cornelius, L. / Qin, L.Y. / Ruan, Z. / Neels, J. / Beaudoin-Bertrand, M. / Srivastava, A.S. / Li, L. / Cherney, R.J. / Gong, H. / Watterson, S.H. / Weigelt, C. / Gillooly, K.M. / McIntyre, K.W. / Xie, J.H. / Obermeier, M.T. / Fura, A. / Sleczka, B. / Stefanski, K. / Fancher, R.M. / Padmanabhan, S. / Rp, T. / Kundu, I. / Rajareddy, K. / Smith, R. / Hennan, J.K. / Xing, D. / Fan, J. / Levesque, P.C. / Ruan, Q. / Pitt, S. / Zhang, R. / Pedicord, D. / Pan, J. / Yarde, M. / Lu, H. / Lippy, J. / Goldstine, C. / Skala, S. / Rampulla, R.A. / Mathur, A. / Gupta, A. / Arunachalam, P.N. / Sack, J.S. / Muckelbauer, J.K. / Cvijic, M.E. / Salter-Cid, L.M. / Bhide, R.S. / Poss, M.A. / Hynes, J. / Carter, P.H. / Macor, J.E. / Ruepp, S. / Schieven, G.L. / Tino, J.A.
History
DepositionApr 26, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Mar 13, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
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 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
B: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,4793
Polymers136,9532
Non-polymers5271
Water43224
1
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,4852
Polymers115,9591
Non-polymers5271
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Phosphatidylinositol 3-kinase regulatory subunit alpha


Theoretical massNumber of molelcules
Total (without water)20,9941
Polymers20,9941
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4100 Å2
ΔGint-20 kcal/mol
Surface area49380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.847, 108.579, 142.734
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 delta isoform / PtdIns-3-kinase subunit delta / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit delta / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit delta / p110delta


Mass: 115958.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CD / Production host: unidentified baculovirus
References: UniProt: O00329, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / 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


Mass: 20993.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: unidentified baculovirus / References: UniProt: P27986
#3: Chemical ChemComp-9EM / 4-acetyl-1-(3-{4-amino-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}phenyl)-3,3-dimethylpiperazin-2-one


Mass: 526.514 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25F3N8O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 24 / 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: 2.6 Å3/Da / Density % sol: 53.2 %
Crystal growTemperature: 300 K / Method: vapor diffusion / Details: NULL, VAPOR DIFFUSION, TEMPERATURE 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 X 1M / Detector: PIXEL / Date: Dec 12, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→86.39 Å / Num. obs: 34160 / % possible obs: 96.3 % / Observed criterion σ(I): 0 / Redundancy: 2.8 % / Biso Wilson estimate: 89.13 Å2 / Rmerge(I) obs: 0.034 / Net I/σ(I): 22.27
Reflection shellResolution: 2.8→3.05 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.44 / Num. unique all: 7593 / % possible all: 97.8

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
BUSTER2.11.7refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→46.6 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.881 / SU R Cruickshank DPI: 2.823 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.984 / SU Rfree Blow DPI: 0.384 / SU Rfree Cruickshank DPI: 0.392
RfactorNum. reflection% reflectionSelection details
Rfree0.279 709 2.08 %RANDOM
Rwork0.208 ---
obs0.21 34158 96.3 %-
Displacement parametersBiso mean: 87.32 Å2
Baniso -1Baniso -2Baniso -3
1--14.0135 Å20 Å20 Å2
2---10.345 Å20 Å2
3---24.3585 Å2
Refine analyzeLuzzati coordinate error obs: 0.4 Å
Refinement stepCycle: LAST / Resolution: 2.8→46.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8386 0 38 24 8448
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018599HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1511661HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2912SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes203HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1295HARMONIC5
X-RAY DIFFRACTIONt_it8599HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.52
X-RAY DIFFRACTIONt_other_torsion20.74
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1120SEMIHARMONIC5
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_contact9825SEMIHARMONIC4
LS refinement shellResolution: 2.8→2.89 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.3073 -2.12 %
Rwork0.2516 2910 -
all0.2526 2973 -
obs--98.54 %

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