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- PDB-5ubt: CRYSTAL STRUCTURE OF PI3K DELTA IN COMPLEX WITH A 7-(3-(PIPERAZIN... -

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Entry
Database: PDB / ID: 5ubt
TitleCRYSTAL STRUCTURE OF PI3K DELTA IN COMPLEX WITH A 7-(3-(PIPERAZIN-1-YL)PHENYL)PYRROLO[2,1-F][1,2,4] TRIAZIN-4-AMINE DERIVIATINE
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 / positive regulation of epithelial tube formation / perinuclear endoplasmic reticulum membrane / natural killer cell chemotaxis / regulation of toll-like receptor 4 signaling pathway / neutrophil extravasation / positive regulation of neutrophil apoptotic process ...B cell chemotaxis / mast cell differentiation / mast cell chemotaxis / natural killer cell differentiation / positive regulation of epithelial tube formation / perinuclear endoplasmic reticulum membrane / natural killer cell chemotaxis / regulation of toll-like receptor 4 signaling pathway / neutrophil extravasation / positive regulation of neutrophil apoptotic process / 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 / 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 / T cell chemotaxis / natural killer cell activation / cis-Golgi network / Activated NTRK3 signals through PI3K / ErbB-3 class receptor binding / RHOF GTPase cycle / kinase activator activity / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / Nephrin family interactions / RND1 GTPase cycle / Costimulation by the CD28 family / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / RND2 GTPase cycle / MET activates PI3K/AKT signaling / PI3K/AKT activation / RND3 GTPase cycle / positive regulation of leukocyte migration / positive regulation of filopodium assembly / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / negative regulation of stress fiber assembly / phosphatidylinositol 3-kinase / growth hormone receptor signaling pathway / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / RHOV GTPase cycle / 1-phosphatidylinositol-3-kinase activity / RHOB GTPase cycle / negative regulation of cell-matrix adhesion / mast cell degranulation / Signaling by ALK / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / B cell activation / 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 / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / RHOG GTPase cycle / T cell differentiation / RET signaling / extrinsic apoptotic signaling pathway via death domain receptors / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / RHOA GTPase cycle / RAC2 GTPase cycle / RAC3 GTPase cycle / Role of phospholipids in phagocytosis / GAB1 signalosome / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / positive regulation of lamellipodium assembly / phosphatidylinositol 3-kinase binding / 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 / SH2 domain / Src homology 3 domains / 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-85S / 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: 2.83 Å
AuthorsSack, J.S.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3K delta inhibitors.
Authors: Qin, L.Y. / Ruan, Z. / Cherney, R.J. / Dhar, T.G. / Neels, J. / Weigelt, C.A. / Sack, J.S. / Srivastava, A.S. / Cornelius, L.A. / Tino, J.A. / Stefanski, K. / Gu, X. / Xie, J. / Susulic, V. ...Authors: Qin, L.Y. / Ruan, Z. / Cherney, R.J. / Dhar, T.G. / Neels, J. / Weigelt, C.A. / Sack, J.S. / Srivastava, A.S. / Cornelius, L.A. / Tino, J.A. / Stefanski, K. / Gu, X. / Xie, J. / Susulic, V. / Yang, X. / Yarde-Chinn, M. / Skala, S. / Bosnius, R. / Goldstein, C. / Davies, P. / Ruepp, S. / Salter-Cid, L. / Bhide, R.S. / Poss, M.A.
History
DepositionDec 21, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2017Group: Database references
Revision 1.2Mar 6, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
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)137,1623
Polymers136,6752
Non-polymers4871
Water23413
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4170 Å2
ΔGint-20 kcal/mol
Surface area50930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.662, 108.603, 142.903
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: 20716.379 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-85S / 1-[4-(3-{4-amino-5-[1-(oxan-4-yl)-1H-pyrazol-5-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}phenyl)piperazin-1-yl]ethan-1-one


Mass: 486.569 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30N8O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 13 / 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: 293 K / Method: vapor diffusion / Details: NULL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / 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: 2.83→86.47 Å / Num. obs: 34340 / % possible obs: 97.1 % / Observed criterion σ(I): 0 / Redundancy: 2.8 % / Biso Wilson estimate: 102.09 Å2 / Rmerge(I) obs: 0.03 / Net I/σ(I): 1
Reflection shellResolution: 2.83→3.08 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.441 / % possible all: 98.3

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.83→37.86 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.905 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.377
RfactorNum. reflection% reflectionSelection details
Rfree0.268 688 2.06 %RANDOM
Rwork0.215 ---
obs0.216 33327 97.1 %-
Displacement parametersBiso mean: 104.62 Å2
Baniso -1Baniso -2Baniso -3
1--19.2562 Å20 Å20 Å2
2---10.6168 Å20 Å2
3---29.873 Å2
Refine analyzeLuzzati coordinate error obs: 0.43 Å
Refinement stepCycle: LAST / Resolution: 2.83→37.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8050 0 36 13 8099
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0098692HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0111757HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3051SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes220HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1276HARMONIC5
X-RAY DIFFRACTIONt_it8692HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.19
X-RAY DIFFRACTIONt_other_torsion20.46
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1119SEMIHARMONIC5
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_contact9567SEMIHARMONIC4
LS refinement shellResolution: 2.83→2.92 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.386 -2.56 %
Rwork0.2726 2779 -
all0.2752 2852 -
obs--97.47 %

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