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- PDB-2y3a: Crystal structure of p110beta in complex with icSH2 of p85beta an... -

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Basic information

Entry
Database: PDB / ID: 2y3a
TitleCrystal structure of p110beta in complex with icSH2 of p85beta and the drug GDC-0941
Components
  • PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT BETA
  • PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT BETA ISOFORM
KeywordsTRANSFERASE / PHOSPHOINOSITIDE 3-KINASE / RTK
Function / homology
Function and homology information


RHOJ GTPase cycle / IRS-mediated signalling / Signaling by ALK / Signaling by LTK / Tie2 Signaling / RND3 GTPase cycle / PI3K/AKT activation / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / RHOF GTPase cycle ...RHOJ GTPase cycle / IRS-mediated signalling / Signaling by ALK / Signaling by LTK / Tie2 Signaling / RND3 GTPase cycle / PI3K/AKT activation / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / RHOF GTPase cycle / RHOU GTPase cycle / RAC3 GTPase cycle / Downstream signal transduction / CDC42 GTPase cycle / RAC2 GTPase cycle / GPVI-mediated activation cascade / Interleukin-7 signaling / RHOD GTPase cycle / negative regulation of sprouting angiogenesis / Signaling by SCF-KIT / RND2 GTPase cycle / RND1 GTPase cycle / Role of phospholipids in phagocytosis / negative regulation of vascular endothelial growth factor signaling pathway / Co-stimulation by ICOS / RAC1 GTPase cycle / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / CD28 dependent PI3K/Akt signaling / RHOB GTPase cycle / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / Extra-nuclear estrogen signaling / RAF/MAP kinase cascade / G alpha (q) signalling events / positive regulation of neutrophil apoptotic process / PIP3 activates AKT signaling / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / Downstream TCR signaling / RHOA GTPase cycle / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of cell-matrix adhesion / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / regulation of actin filament polymerization / phosphatidylinositol 3-kinase regulatory subunit binding / embryonic cleavage / VEGFA-VEGFR2 Pathway / regulation of stress fiber assembly / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / endothelial cell proliferation / angiogenesis involved in wound healing / DAP12 signaling / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-3-kinase activity / natural killer cell mediated cytotoxicity / intracellular glucose homeostasis / phosphatidylinositol phosphate biosynthetic process / homophilic cell-cell adhesion / positive regulation of Rac protein signal transduction / insulin receptor substrate binding / regulation of protein localization to plasma membrane / negative regulation of MAPK cascade / phosphotyrosine residue binding / positive regulation of endothelial cell migration / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell adhesion / response to endoplasmic reticulum stress / response to ischemia / phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor tyrosine kinase binding / platelet activation / positive regulation of protein import into nucleus / autophagy / endocytosis / cellular response to insulin stimulus / intracellular calcium ion homeostasis / positive regulation of nitric oxide biosynthetic process / insulin receptor signaling pathway / protein transport / midbody / protein phosphatase binding / non-specific serine/threonine protein kinase / regulation of autophagy / protein heterodimerization activity / protein serine kinase activity / focal adhesion / positive regulation of gene expression / nucleolus / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus / cytosol
Similarity search - Function
PI3Kbeta, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit beta, SH3 domain / Ubiquitin-like (UB roll) - #770 / Helix Hairpins - #1490 / 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-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 ...PI3Kbeta, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit beta, SH3 domain / Ubiquitin-like (UB roll) - #770 / Helix Hairpins - #1490 / 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-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) / 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. / Rho GTPase activation protein / 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. / SH2 domain / SHC Adaptor Protein / 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Ubiquitin-like (UB roll) / Helix Hairpins / 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-GD9 / Phosphatidylinositol 3-kinase regulatory subunit beta / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform
Similarity search - Component
Biological speciesMUS MUSCULUS (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsZhang, X. / Vadas, O. / Perisic, O. / Williams, R.L.
CitationJournal: Mol.Cell / Year: 2011
Title: Structure of Lipid Kinase P110Beta-P85Beta Elucidates an Unusual Sh2-Domain-Mediated Inhibitory Mechanism.
Authors: Zhang, X. / Vadas, O. / Perisic, O. / Anderson, K.E. / Clark, J. / Hawkins, P.T. / Stephens, L.R. / Williams, R.L.
History
DepositionDec 20, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 16, 2011Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 3, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc / pdbx_database_status
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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 BETA ISOFORM
B: PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT BETA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)161,1023
Polymers160,5892
Non-polymers5141
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5840 Å2
ΔGint-25.6 kcal/mol
Surface area58210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)134.314, 134.314, 428.062
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT BETA ISOFORM / PI3-KINASE SUBUNIT BETA / PI3K-BETA / PTDINS-3-KINASE SUBUNIT BETA / PHOSPHATIDYLINOSITOL-4 / 5- ...PI3-KINASE SUBUNIT BETA / PI3K-BETA / PTDINS-3-KINASE SUBUNIT BETA / PHOSPHATIDYLINOSITOL-4 / 5-BISPHOSPHATE 3-KINASE 110 KDA CATALYTIC SUBUNIT BETA / PTDINS-3-KINASE SUBUNIT P110-BETA / PIK3CA


Mass: 125242.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Plasmid: PFASTBAC-HTB / Cell line (production host): Sf9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q8BTI9, nicotinate riboside kinase
#2: Protein PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT BETA / PI3-KINASE REGULATORY SUBUNIT BETA / PI3K REGULATORY SUBUNIT BETA / PTDINS-3-KINASE REGULATORY ...PI3-KINASE REGULATORY SUBUNIT BETA / PI3K REGULATORY SUBUNIT BETA / PTDINS-3-KINASE REGULATORY SUBUNIT BETA / PHOSPHATIDYLINOSITOL 3-KINASE 85 KDA REGULATORY SUBUNIT BETA / PI3-KINASE SUBUNIT P85-BETA / PTDINS-3-KINASE REGULATORY SUBUNIT P85-BETA / PIK3R2


Mass: 35346.574 Da / Num. of mol.: 1 / Fragment: ICSH2 DOMAIN, RESIDUES 423-722
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Plasmid: PFASTBAC-1 / Cell line (production host): Sf9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: O08908
#3: Chemical ChemComp-GD9 / 2-(1H-indazol-4-yl)-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-4-morpholin-4-yl-thieno[3,2-d]pyrimidine


Mass: 513.636 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27N7O3S2
Sequence detailsN-TERMINAL 6XHIS TAG

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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: 3.48 Å3/Da / Density % sol: 64.71 % / Description: NONE
Crystal growpH: 6
Details: PROTEIN WAS CRYSTALLIZED FROM 12% PEG 3350, 0.1 M POTASSIUM CITRATE PH 6, 0.4 M LITHIUM SULFATE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9765
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 5, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 3.3→44 Å / Num. obs: 34250 / % possible obs: 98.9 % / Observed criterion σ(I): 1 / Redundancy: 5.2 % / Biso Wilson estimate: 90.8 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 10.4
Reflection shellResolution: 3.3→3.5 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.67 / Mean I/σ(I) obs: 1.9 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.8.0refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WHG

2whg


Resolution: 3.3→44.68 Å / Cor.coef. Fo:Fc: 0.8743 / Cor.coef. Fo:Fc free: 0.8398 / Cross valid method: THROUGHOUT / σ(F): 0
Details: RESIDUES 1-12, 228-234, 299-3 -1064 ARE DISORDERED.
RfactorNum. reflection% reflectionSelection details
Rfree0.296 1764 5.15 %RANDOM
Rwork0.234 ---
obs0.2372 34250 --
Displacement parametersBiso mean: 127.72 Å2
Baniso -1Baniso -2Baniso -3
1--27.9399 Å20 Å20 Å2
2---27.9399 Å20 Å2
3---55.8799 Å2
Refine analyzeLuzzati coordinate error obs: 0.906 Å
Refinement stepCycle: LAST / Resolution: 3.3→44.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9813 0 35 0 9848
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110052HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.3513582HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3595SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes284HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1428HARMONIC5
X-RAY DIFFRACTIONt_it10052HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.62
X-RAY DIFFRACTIONt_other_torsion25.33
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1276SEMIHARMONIC5
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_contact12152SEMIHARMONIC4
LS refinement shellResolution: 3.3→3.4 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.3027 137 5.17 %
Rwork0.263 2514 -
all0.265 2651 -

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