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- PDB-2v1y: Structure of a phosphoinositide 3-kinase alpha adaptor-binding do... -

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Basic information

Entry
Database: PDB / ID: 2v1y
TitleStructure of a phosphoinositide 3-kinase alpha adaptor-binding domain (ABD) in a complex with the iSH2 domain from p85 alpha
Components
  • PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT ALPHA
  • PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT ALPHA ISOFORM
KeywordsTRANSFERASE / KINASE / CANCER / SH2 DOMAIN / SH3 DOMAIN / ONCOGENIC MUTATIONS / HOST-VIRUS INTERACTION / PHOSPHORYLATION / DISEASE MUTATION / PHOSPHOINOSITIDE / PHOSPHOLIPID / PHOSPHOLIPID SIGNALLING / PHOSPHOINOSITIDE 3-KINASE / SIGNAL TRANSDUCTION
Function / homology
Function and homology information


: / : / : / : / PI3K events in ERBB4 signaling / GAB1 signalosome / PI3K events in ERBB2 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / IRS-mediated signalling / GPVI-mediated activation cascade ...: / : / : / : / PI3K events in ERBB4 signaling / GAB1 signalosome / PI3K events in ERBB2 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / IRS-mediated signalling / GPVI-mediated activation cascade / Signaling by SCF-KIT / Downstream signal transduction / PI3K/AKT activation / Role of phospholipids in phagocytosis / Tie2 Signaling / Role of LAT2/NTAL/LAB on calcium mobilization / Costimulation by the CD28 family / CD28 dependent PI3K/Akt signaling / Interleukin receptor SHC signaling / PI-3K cascade:FGFR1 / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR3 / PI-3K cascade:FGFR4 / PI3K Cascade / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Synthesis of PIPs at the plasma membrane / DAP12 signaling / Regulation of signaling by CBL / positive regulation of gene expression via chromosomal CpG island demethylation / perinuclear endoplasmic reticulum membrane / RET signaling / regulation of toll-like receptor 4 signaling pathway / Interleukin-3, Interleukin-5 and GM-CSF signaling / VEGFA-VEGFR2 Pathway / phosphatidylinositol kinase activity / phosphatidylinositol 3-kinase regulator activity / 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 / cis-Golgi network / Activated NTRK3 signals through PI3K / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / RHOF GTPase cycle / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / 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 / phosphatidylinositol 3-kinase complex / Nephrin family interactions / RND1 GTPase cycle / Extra-nuclear estrogen signaling / 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 / G alpha (q) signalling events / negative regulation of stress fiber assembly / 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 / Signaling by ALK / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / 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
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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain ...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 / 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 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 / SH2 domain / 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 / Helix Hairpins / Armadillo-type fold / Ubiquitin-like domain superfamily / Roll / Protein kinase-like domain superfamily / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesBOS TAURUS (cattle)
HOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MAD / Resolution: 2.4 Å
AuthorsMiled, N. / Yan, Y. / Hon, W.C. / Perisic, O. / Zvelebil, M. / Inbar, Y. / Schneidman-Duhovny, D. / Wolfson, H.J. / Backer, J.M. / Williams, R.L.
CitationJournal: Science / Year: 2007
Title: Mechanism of Two Classes of Cancer Mutations in the Phosphoinositide 3-Kinase Catalytic Subunit.
Authors: Miled, N. / Yan, Y. / Hon, W.C. / Perisic, O. / Zvelebil, M. / Inbar, Y. / Schneidman-Duhovny, D. / Wolfson, H.J. / Backer, J.M. / Williams, R.L.
History
DepositionMay 30, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance

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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
B: PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT ALPHA


Theoretical massNumber of molelcules
Total (without water)34,0452
Polymers34,0452
Non-polymers00
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)58.799, 62.000, 74.654
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 / PHOSPHOINOSITIDE 3-KINASE P110 ALPHA / PI3-KINASE P110 SUBUNIT ALPHA / PTDINS-3-KINASE P110 / PI3K


Mass: 12821.479 Da / Num. of mol.: 1 / Fragment: ADAPTOR-BINDING DOMAIN, RESIDUES 1-108
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) BOS TAURUS (cattle)
Description: CHAIN A IS THE ADAPTOR-BINDING DOMAIN FROM BOVINE P110 ALPHA
Plasmid: POPCG / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): B834(DE3)
References: UniProt: P32871, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Protein PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT ALPHA / PHOSPHOINOSITIDE 3-KINASE P85 ALPHA / PI3-KINASE P85-SUBUNIT ALPHA / PTDINS-3-KINASE P85-ALPHA / PI3K


Mass: 21223.402 Da / Num. of mol.: 1 / Fragment: INTER-SH2 DOMAIN (ISH2), RESIDUES 431-600
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human)
Description: CHAIN B IS THE ISH2 DOMAIN FROM HUMAN P85 ALPHA
Plasmid: POPCG / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): B834(DE3)
References: UniProt: P27986, phosphatidylinositol-4,5-bisphosphate 3-kinase
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O
Compound detailsPHOSPHORYLATES PTDINS, PTDINS4P AND PTDINS(4,5)P2. BINDS TO ACTIVATED (PHOSPHORYLATED) PROTEIN-TYR ...PHOSPHORYLATES PTDINS, PTDINS4P AND PTDINS(4,5)P2. BINDS TO ACTIVATED (PHOSPHORYLATED) PROTEIN-TYR KINASES, THROUGH ITS SH2 DOMAIN, AND ACTS AS AN ADAPTER, MEDIATING THE ASSOCIATION OF THE P110 CATALYTIC UNIT TO THE PLASMA MEMBRANE
Sequence detailsADAPTOR-BINDING DOMAIN, RESIDUES 1-108 RESIDUES 431-600 OF HUMAN P85 ALPHA

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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: 2.18 Å3/Da / Density % sol: 43 %
Crystal growpH: 7
Details: 0.2M MG(NO3)2, 20% PEG3350 (HAMPTON), 5MM TRIS-HCL PH 7.0 (25C), 5% GLYCEROL AND 5MM FRESH DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9794,0.9393
DetectorType: ADSC CCD / Detector: CCD / Details: BENT MIRROR
RadiationMonochromator: SI(111) / Protocol: MAD / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
10.97941
20.93931
ReflectionResolution: 2.4→47.67 Å / Num. obs: 10926 / % possible obs: 98.3 % / Observed criterion σ(I): -3 / Redundancy: 3.53 % / Biso Wilson estimate: 45 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 13.48
Reflection shellResolution: 2.4→2.42 Å / Redundancy: 3.58 % / Rmerge(I) obs: 0.2 / Mean I/σ(I) obs: 3.32 / % possible all: 100

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
SnBphasing
autoSHARPphasing
REFMAC5.1.24refinement
RefinementMethod to determine structure: MAD / Resolution: 2.4→47.67 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.882 / SU B: 9.151 / SU ML: 0.215 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.71 / ESU R Free: 0.333
Stereochemistry target values: MAXIMUM LIKELIHOODWITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.292 521 4.8 %RANDOM
Rwork0.233 ---
obs0.236 10385 97.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 30.99 Å2
Baniso -1Baniso -2Baniso -3
1-0.33 Å20 Å20 Å2
2--2.03 Å20 Å2
3----2.36 Å2
Refinement stepCycle: LAST / Resolution: 2.4→47.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2217 0 0 17 2234
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222252
X-RAY DIFFRACTIONr_bond_other_d0.0020.022056
X-RAY DIFFRACTIONr_angle_refined_deg1.2591.9643016
X-RAY DIFFRACTIONr_angle_other_deg0.78534812
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4525258
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0720.2322
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022437
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02455
X-RAY DIFFRACTIONr_nbd_refined0.1990.2472
X-RAY DIFFRACTIONr_nbd_other0.2260.22149
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0870.21399
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1190.224
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2230.220
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2790.263
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2650.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7011.51300
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.37122112
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.9513952
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.3444.5904
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: 2.4→2.46 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.246 35
Rwork0.231 782
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)
12.3613-0.3209-0.04972.1215-0.41724.0073-0.06890.01670.18470.06390.02610.0007-0.1550.20640.04280.0145-0.0112-0.00540.06110.02120.06153.702860.667113.9575
2-2.1467-7.86318.531517.1876-4.308516.364-0.04380.2970.7349-0.7157-0.0213-0.91460.83580.29840.06510.1351000.1347-0.00010.134999.00918.2357-38.9518
311.8007-7.4162-9.91084.71976.47628.56330.1017-0.08160.0066-0.1183-0.0631-0.024-0.18110.0674-0.03860.09450.02420.0070.06740.05810.052365.788651.3096-14.1316
41.4606-0.9912-1.75390.31681.25911.95730.03020.04940.13860.00130.068-0.1324-0.0397-0.0079-0.09820.19350.03280.00980.11940.02460.168968.319451.0904-17.8304
528.1263-13.907421.63915.5963-4.80447.6572-0.07270.3891.58631.2639-0.2303-2.3947-0.0248-0.37480.30290.13440.0019-0.00040.13480.00160.13497.434133.6587-31.2563
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A20 - 105
2X-RAY DIFFRACTION2B431 - 441
3X-RAY DIFFRACTION3B442 - 510
4X-RAY DIFFRACTION4B518 - 595
5X-RAY DIFFRACTION5B596 - 600

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