EzCatDB: M00043
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DB codeM00043
RLCP classification3.103.106000.1163 : Transfer
CATH domainDomain 13.10.20.90 : Ubiquitin-like (UB roll)
Domain 22.60.40.150 : Immunoglobulin-like
Domain 31.25.40.70 : Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat
Domain 43.30.1010.10 : Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4Catalytic domain
Domain 51.10.1070.11 : Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5Catalytic domain
Domain 62.30.30.40 : SH3 type barrels.
Domain 71.10.555.10 : Phosphatidylinositol 3-kinase; Chain A
Domain 83.30.505.10 : SHC Adaptor Protein
Domain 93.30.505.10 : SHC Adaptor Protein
E.C.2.7.1.153

CATH domainRelated DB codes (homologues)
2.30.30.40 : SH3 type barrels.M00183,M00130,T00256,M00304,M00335
2.60.40.150 : Immunoglobulin-likeM00221,M00183,M00118
3.30.505.10 : SHC Adaptor ProteinM00183,M00130,M00148,T00256,M00304,M00333,M00339,M00344,T00221

Enzyme Name
UniProtKBKEGG

P32871O02697P48736P23727P27986
Protein namePhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoformPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoformPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoformPhosphatidylinositol 3-kinase regulatory subunit alphaPhosphatidylinositol 3-kinase regulatory subunit alphaphosphatidylinositol-4,5-bisphosphate 3-kinase
type I phosphoinositide 3-kinase
SynonymsPI3-kinase subunit alpha
PI3K-alpha
PI3Kalpha
PtdIns-3-kinase subunit alpha
EC 2.7.1.153
Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha
PtdIns-3-kinase subunit p110-alpha
p110alpha
Phosphoinositide-3-kinase catalytic alpha polypeptide
Serine/threonine protein kinase PIK3CA
EC 2.7.11.1
PI3-kinase subunit gamma
PI3K-gamma
PI3Kgamma
PtdIns-3-kinase subunit gamma
EC 2.7.1.153
Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma
PtdIns-3-kinase subunit p110-gamma
p110gamma
Phosphoinositide-3-kinase catalytic gamma polypeptide
Serine/threonine protein kinase PIK3CG
EC 2.7.11.1
p120-PI3K
PI3-kinase subunit gamma
PI3K-gamma
PI3Kgamma
PtdIns-3-kinase subunit gamma
EC 2.7.1.153
Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma
PtdIns-3-kinase subunit p110-gamma
p110gamma
Phosphoinositide-3-kinase catalytic gamma polypeptide
Serine/threonine protein kinase PIK3CG
EC 2.7.11.1
p120-PI3K
PI3-kinase regulatory subunit alpha
PI3K regulatory subunit alpha
PtdIns-3-kinase regulatory subunit alpha
Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha
PI3-kinase subunit p85-alpha
PtdIns-3-kinase regulatory subunit p85-alpha
PI3-kinase regulatory subunit alpha
PI3K regulatory subunit alpha
PtdIns-3-kinase regulatory subunit alpha
Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha
PI3-kinase subunit p85-alpha
PtdIns-3-kinase regulatory subunit p85-alpha
RefSeqNP_776999.1 (Protein)
NM_174574.1 (DNA/RNA sequence)
NP_999104.1 (Protein)
NM_213939.1 (DNA/RNA sequence)
NP_002640.2 (Protein)
NM_002649.2 (DNA/RNA sequence)
NP_777000.1 (Protein)
NM_174575.1 (DNA/RNA sequence)
NP_001229395.1 (Protein)
NM_001242466.1 (DNA/RNA sequence)
NP_852556.2 (Protein)
NM_181504.3 (DNA/RNA sequence)
NP_852664.1 (Protein)
NM_181523.2 (DNA/RNA sequence)
NP_852665.1 (Protein)
NM_181524.1 (DNA/RNA sequence)
PfamPF00454 (PI3_PI4_kinase)
PF00792 (PI3K_C2)
PF02192 (PI3K_p85B)
PF00794 (PI3K_rbd)
PF00613 (PI3Ka)
[Graphical view]
PF00454 (PI3_PI4_kinase)
PF00792 (PI3K_C2)
PF00794 (PI3K_rbd)
PF00613 (PI3Ka)
[Graphical view]
PF00454 (PI3_PI4_kinase)
PF00792 (PI3K_C2)
PF00794 (PI3K_rbd)
PF00613 (PI3Ka)
[Graphical view]
PF00620 (RhoGAP)
PF00017 (SH2)
PF07653 (SH3_2)
[Graphical view]
PF00620 (RhoGAP)
PF00017 (SH2)
PF07653 (SH3_2)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00562Inositol phosphate metabolism
MAP04070Phosphatidylinositol signaling system

UniProtKB:Accession NumberP32871O02697P48736P23727P27986
Entry namePK3CA_BOVINPK3CG_PIGPK3CG_HUMANP85A_BOVINP85A_HUMAN
ActivityATP + 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5- trisphosphate.ATP + 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5- trisphosphate.ATP + 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5- trisphosphate.

SubunitHeterodimer of a p110 (catalytic) and a p85 (regulatory) subunit. Binds to IRS1 in nuclear extracts. Interacts with RUFY3 (By similarity).Heterodimer of a catalytic subunit (PIK3CG/p120) and a regulatory (PIK3R5a/p101) subunit.Heterodimer of a catalytic subunit (PIK3CG/p120) and a regulatory (PIK3R5a/p101) subunit.Heterodimer of a p110 (catalytic) and a p85 (regulatory) subunits. Interacts with phosphorylated LAT, LAX1, TRAT1 and LIME1 upon TCR and/or BCR activation. Interacts with CBLB. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with SOCS7. Interacts with IRS1 and phosphorylated IRS4. Interacts with NISCH, RUFY3 and HCST (By similarity).Heterodimer of a p110 (catalytic) and a p85 (regulatory) subunits. Interacts with phosphorylated TOM1L1. Interacts with phosphorylated LIME1 upon TCR and/or BCR activation. Interacts with SOCS7. Interacts with RUFY3 (By similarity). Interacts with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation. Interacts with CBLB. Interacts with HIV-1 Nef to activate the Nef associated p21-activated kinase (PAK). This interaction depends on the C- terminus of both proteins and leads to increased production of HIV. Interacts with HCV NS5A. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with IRS1 and phosphorylated IRS4, as well as with NISCH and HCST.
Subcellular location




Cofactor





Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00305C00002C04637C00008C05981
CompoundMagnesiumATP1-phosphatidyl-1D-myo-inositol 4,5-bisphosphateADP1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
Typedivalent metal (Ca2+, Mg2+)amine group,nucleotidecarbohydrate,lipid,phosphate group/phosphate ionamine group,nucleotidecarbohydrate,lipid,phosphate group/phosphate ion
ChEBI18420
15422

16761

PubChem888
5957

6022

             
1e7uA01UnboundUnboundUnboundUnboundUnbound
1e7vA01UnboundUnboundUnboundUnboundUnbound
1e8wA01UnboundUnboundUnboundUnboundUnbound
1e8xA01UnboundUnboundUnboundUnboundUnbound
1e90A01UnboundUnboundUnboundUnboundUnbound
1qmmA01UnboundUnboundUnboundUnboundUnbound
1e8yA01UnboundUnboundUnboundUnboundUnbound
1e8zA01UnboundUnboundUnboundUnboundUnbound
1he8A01UnboundUnboundUnboundUnboundUnbound
1e7uA02UnboundUnboundUnboundUnboundUnbound
1e7vA02UnboundUnboundUnboundUnboundUnbound
1e8wA02UnboundUnboundUnboundUnboundUnbound
1e8xA02UnboundUnboundUnboundUnboundUnbound
1e90A02UnboundUnboundUnboundUnboundUnbound
1qmmA02UnboundUnboundUnboundUnboundUnbound
1e8yA02UnboundUnboundUnboundUnboundUnbound
1e8zA02UnboundUnboundUnboundUnboundUnbound
1he8A02UnboundUnboundUnboundUnboundUnbound
1e7uA03UnboundUnboundUnboundUnboundUnbound
1e7vA03UnboundUnboundUnboundUnboundUnbound
1e8wA03UnboundUnboundUnboundUnboundUnbound
1e8xA03UnboundUnboundUnboundUnboundUnbound
1e90A03UnboundUnboundUnboundUnboundUnbound
1qmmA03UnboundUnboundUnboundUnboundUnbound
1e8yA03UnboundUnboundUnboundUnboundUnbound
1e8zA03UnboundUnboundUnboundUnboundUnbound
1he8A03UnboundUnboundUnboundUnboundUnbound
1e7uA04UnboundUnboundAnalogue:KWTUnboundUnbound
1e7vA04UnboundUnboundUnboundUnboundUnbound
1e8wA04UnboundUnboundUnboundUnboundUnbound
1e8xA04UnboundBound:ATPUnboundUnboundUnbound
1e90A04UnboundUnboundUnboundUnboundUnbound
1qmmA04UnboundBound:ATPUnboundUnboundUnbound
1e8yA04UnboundUnboundUnboundUnboundUnbound
1e8zA04UnboundUnboundUnboundUnboundUnbound
1he8A04UnboundUnboundUnboundUnboundUnbound
1e7uA05UnboundUnboundUnboundUnboundUnbound
1e7vA05UnboundUnboundUnboundUnboundUnbound
1e8wA05UnboundUnboundUnboundUnboundUnbound
1e8xA05Analogue:2x_LUUnboundUnboundUnboundUnbound
1e90A05UnboundUnboundUnboundUnboundUnbound
1qmmA05Analogue:2x_LUUnboundUnboundUnboundUnbound
1e8yA05UnboundUnboundUnboundUnboundUnbound
1e8zA05UnboundUnboundUnboundUnboundUnbound
1he8A05UnboundUnboundUnboundUnboundUnbound
1pnjAUnboundUnboundUnboundUnboundUnbound
2pniAUnboundUnboundUnboundUnboundUnbound
1phtAUnboundUnboundUnboundUnboundUnbound
1pksAUnboundUnboundUnboundUnboundUnbound
1pktAUnboundUnboundUnboundUnboundUnbound
1pbwAUnboundUnboundUnboundUnboundUnbound
1pbwBUnboundUnboundUnboundUnboundUnbound
1oo3AUnboundUnboundUnboundUnboundUnbound
1oo4AUnboundUnboundUnboundUnboundUnbound
2pnaAUnboundUnboundUnboundUnboundUnbound
2pnbAUnboundUnboundUnboundUnboundUnbound
1bfiAUnboundUnboundUnboundUnboundUnbound
1bfjAUnboundUnboundUnboundUnboundUnbound
1qadAUnboundUnboundUnboundUnboundUnbound
1h9oAUnboundUnboundUnboundUnboundUnbound
1picAUnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
(See comments)
pdbCatalytic residuesCofactor-binding residuescomment
           
1e7uA01 
 
 
1e7vA01 
 
 
1e8wA01 
 
 
1e8xA01 
 
 
1e90A01 
 
 
1qmmA01 
 
 
1e8yA01 
 
 
1e8zA01 
 
 
1he8A01 
 
 
1e7uA02 
 
mutant R505A
1e7vA02 
 
mutant R505A
1e8wA02 
 
mutant R505A
1e8xA02 
 
mutant R505A
1e90A02 
 
mutant R505A
1qmmA02 
 
mutant R505A
1e8yA02 
 
mutant P1M
1e8zA02 
 
mutant P1M
1he8A02 
 
mutant R505A
1e7uA03 
 
 
1e7vA03 
 
 
1e8wA03 
 
 
1e8xA03 
 
 
1e90A03 
 
 
1qmmA03 
 
 
1e8yA03 
 
 
1e8zA03 
 
 
1he8A03 
 
 
1e7uA04SER 806;LYS 807;LYS 833
ASP 836(Magnesium binding)
 
1e7vA04SER 806;LYS 807;LYS 833
ASP 836(Magnesium binding)
 
1e8wA04SER 806;LYS 807;LYS 833
ASP 836(Magnesium binding)
 
1e8xA04SER 806;LYS 807;LYS 833
ASP 836(Magnesium binding)
 
1e90A04SER 806;LYS 807;LYS 833
ASP 836(Magnesium binding)
 
1qmmA04SER 806;LYS 807;LYS 833
ASP 836(Magnesium binding)
 
1e8yA04SER 806;LYS 807;LYS 833
ASP 836(Magnesium binding)
 
1e8zA04SER 806;LYS 807;LYS 833
ASP 836(Magnesium binding)
 
1he8A04SER 806;LYS 807;LYS 833
ASP 836(Magnesium binding)
 
1e7uA05HIS 948;ASP 950
ASN 951;ASP 964(Magnesium binding)
 
1e7vA05HIS 948;ASP 950
ASN 951;ASP 964(Magnesium binding)
 
1e8wA05HIS 948;ASP 950
ASN 951;ASP 964(Magnesium binding)
 
1e8xA05HIS 948;ASP 950
ASN 951;ASP 964(Magnesium binding)
 
1e90A05HIS 948;ASP 950
ASN 951;ASP 964(Magnesium binding)
 
1qmmA05HIS 948;ASP 950
ASN 951;ASP 964(Magnesium binding)
 
1e8yA05HIS 948;ASP 950
ASN 951;ASP 964(Magnesium binding)
 
1e8zA05HIS 948;ASP 950
ASN 951;ASP 964(Magnesium binding)
 
1he8A05HIS 948;ASP 950
ASN 951;ASP 964(Magnesium binding)
 
1pnjA 
 
 
2pniA 
 
 
1phtA 
 
 
1pksA 
 
 
1pktA 
 
 
1pbwA 
 
 
1pbwB 
 
 
1oo3A 
 
 
1oo4A 
 
 
2pnaA 
 
 
2pnbA 
 
 
1bfiA 
 
 
1bfjA 
 
 
1qadA 
 
 
1h9oA 
 
 
1picA 
 
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[29]p.315
[46]p.428-429

references
[1]
CommentsSTRUCTURE BY NMR OF 314-431
Medline ID92357146
PubMed ID1323062
JournalNature
Year1992
Volume358
Pages684-7
AuthorsBooker GW, Breeze AL, Downing AK, Panayotou G, Gout I, Waterfield MD, Campbell ID
TitleStructure of an SH2 domain of the p85 alpha subunit of phosphatidylinositol-3-OH kinase.
Related PDB2pna,2pnb
Related UniProtKBP23727
[2]
CommentsCIRCULAR DICHROISM AND FLUORESCENCE SPECTROSCOPY
Medline ID93049176
PubMed ID1330535
JournalEMBO J
Year1992
Volume11
Pages4261-72
AuthorsPanayotou G, Bax B, Gout I, Federwisch M, Wroblowski B, Dhand R, Fry MJ, Blundell TL, Wollmer A, Waterfield MD
TitleInteraction of the p85 subunit of PI 3-kinase and its N-terminal SH2 domain with a PDGF receptor phosphorylation site: structural features and analysis of conformational changes.
Related UniProtKBP23727
[3]
CommentsSTRUCTURE BY NMR OF 1-84
Medline ID93272320
PubMed ID7684655
JournalCell
Year1993
Volume73
Pages813-22
AuthorsBooker GW, Gout I, Downing AK, Driscoll PC, Boyd J, Waterfield MD, Campbell ID
TitleSolution structure and ligand-binding site of the SH3 domain of the p85 alpha subunit of phosphatidylinositol 3-kinase.
Related PDB1pnj,2pni
Related UniProtKBP23727
[4]
CommentsSTRUCTURE BY NMR OF 1-79
Medline ID93208889
PubMed ID7681364
JournalCell
Year1993
Volume72
Pages945-52
AuthorsKoyama S, Yu H, Dalgarno DC, Shin TB, Zydowsky LD, Schreiber SL
TitleStructure of the PI3K SH3 domain and analysis of the SH3 family.
Related PDB1pks,1pkt
Related UniProtKBP27986
[5]
CommentsX-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 115-298
Medline ID97121392
PubMed ID8962058
JournalProc Natl Acad Sci U S A
Year1996
Volume93
Pages14373-8
AuthorsMusacchio A, Cantley LC, Harrison SC
TitleCrystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit.
Related PDB1pbw
Related UniProtKBP27986
[6]
CommentsX-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 324-434
Medline ID96185448
PubMed ID8599763
JournalNat Struct Biol
Year1996
Volume3
Pages364-74
AuthorsNolte RT, Eck MJ, Schlessinger J, Shoelson SE, Harrison SC
TitleCrystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes.
Related UniProtKBP27986
[7]
CommentsX-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-85
Medline ID96196433
PubMed ID8648629
JournalJ Mol Biol
Year1996
Volume257
Pages632-43
AuthorsLiang J, Chen JK, Schreiber ST, Clardy J
TitleCrystal structure of P13K SH3 domain at 20 angstroms resolution.
Related PDB1pht
Related UniProtKBP27986
[8]
CommentsSTRUCTURE BY NMR OF 617-724
Medline ID96312955
PubMed ID8670861
JournalEMBO J
Year1996
Volume15
Pages3579-89
AuthorsBreeze AL, Kara BV, Barratt DG, Anderson M, Smith JC, Luke RW, Best JR, Cartlidge SA
TitleStructure of a specific peptide complex of the carboxy-terminal SH2 domain from the p85 alpha subunit of phosphatidylinositol 3-kinase.
Related PDB1pic
Related UniProtKBP27986
[9]
CommentsSTRUCTURE BY NMR OF 321-434
Medline ID97110350
PubMed ID8952511
JournalBiochemistry
Year1996
Volume35
Pages15570-81
AuthorsGunther UL, Liu Y, Sanford D, Bachovchin WW, Schaffhausen B
TitleNMR analysis of interactions of a phosphatidylinositol 3'-kinase SH2 domain with phosphotyrosine peptides reveals interdependence of major binding sites.
Related UniProtKBP23727
[10]
CommentsSTRUCTURE BY NMR OF 91-104
Medline ID97121261
PubMed ID8961927
JournalBiochemistry
Year1996
Volume35
Pages15646-53
AuthorsRenzoni DA, Pugh DJ, Siligardi G, Das P, Morton CJ, Rossi C, Waterfield MD, Campbell ID, Ladbury JE
TitleStructural and thermodynamic characterization of the interaction of the SH3 domain from Fyn with the proline-rich binding site on the p85 subunit of PI3-kinase.
Related UniProtKBP27986
[11]
CommentsVARIANT ILE-326
Medline ID97184306
PubMed ID9032108
JournalDiabetes
Year1997
Volume46
Pages494-501
AuthorsHansen T, Andersen CB, Echwald SM, Urhammer SA, Clausen JO, Vestergaard H, Owens D, Hansen L, Pedersen O
TitleIdentification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index.
Related UniProtKBP27986
[12]
PubMed ID9034995
JournalJ Rheumatol
Year1997
Volume24
Pages341-8
AuthorsJackson JK, Lauener R, Duronio V, Burt HM
TitleThe involvement of phosphatidylinositol 3-kinase in crystal induced human neutrophil activation.
[13]
PubMed ID9391111
JournalProc Natl Acad Sci U S A
Year1997
Volume94
Pages13820-5
AuthorsLi Z, Wahl MI, Eguinoa A, Stephens LR, Hawkins PT, Witte ON
TitlePhosphatidylinositol 3-kinase-gamma activates Bruton's tyrosine kinase in concert with Src family kinases.
[14]
PubMed ID9488453
JournalMol Cell Biol
Year1998
Volume18
Pages1379-87
AuthorsYu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM
TitleRegulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit.
[15]
CommentsSTRUCTURE BY NMR OF 614-724
Medline ID98173872
PubMed ID9512716
JournalJ Mol Biol
Year1998
Volume276
Pages461-78
AuthorsSiegal G, Davis B, Kristensen SM, Sankar A, Linacre J, Stein RC, Panayotou G, Waterfield MD, Driscoll PC
TitleSolution structure of the C-terminal SH2 domain of the p85 alpha regulatory subunit of phosphoinositide 3-kinase.
Related PDB1bfi,1bfj
Related UniProtKBP23727
[16]
PubMed ID9461588
JournalJ Biol Chem
Year1998
Volume273
Pages3994-4000
Authorsvon Willebrand M, Williams S, Saxena M, Gilman J, Tailor P, Jascur T, Amarante-Mendes GP, Green DR, Mustelin T
TitleModification of phosphatidylinositol 3-kinase SH2 domain binding properties by Abl- or Lck-mediated tyrosine phosphorylation at Tyr-688.
[17]
PubMed ID9804776
JournalJ Biol Chem
Year1998
Volume273
Pages30199-203
AuthorsYu J, Wjasow C, Backer JM
TitleRegulation of the p85/p110alpha phosphatidylinositol 3'-kinase. Distinct roles for the n-terminal and c-terminal SH2 domains.
[18]
PubMed ID9677338
JournalBiochem J
Year1998
Volume333
Pages757-63
AuthorsHellyer NJ, Cheng K, Koland JG
TitleErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase.
[19]
PubMed ID9551103
JournalJ Mol Biol
Year1998
Volume276
Pages657-67
AuthorsGuijarro JI, Morton CJ, Plaxco KW, Campbell ID, Dobson CM
TitleFolding kinetics of the SH3 domain of PI3 kinase by real-time NMR combined with optical spectroscopy.
[20]
PubMed ID9539718
JournalProc Natl Acad Sci U S A
Year1998
Volume95
Pages4224-8
AuthorsGuijarro JI, Sunde M, Jones JA, Campbell ID, Dobson CM
TitleAmyloid fibril formation by an SH3 domain.
[21]
PubMed ID9593201
JournalProteins
Year1998
Volume31
Pages309-19
AuthorsKnapp S, Mattson PT, Christova P, Berndt KD, Karshikoff A, Vihinen M, Smith CI, Ladenstein R
TitleThermal unfolding of small proteins with SH3 domain folding pattern.
[22]
PubMed ID9765155
JournalScience
Year1998
Volume282
Pages293-6
AuthorsBondeva T, Pirola L, Bulgarelli-Leva G, Rubio I, Wetzker R, Wymann MP
TitleBifurcation of lipid and protein kinase signals of PI3Kgamma to the protein kinases PKB and MAPK.
[23]
PubMed ID10525402
JournalJ Mol Biol
Year1999
Volume292
Pages763-70
AuthorsHoedemaeker FJ, Siegal G, Roe SM, Driscoll PC, Abrahams JP
TitleCrystal structure of the C-terminal SH2 domain of the p85alpha regulatory subunit of phosphoinositide 3-kinase: an SH2 domain mimicking its own substrate.
[24]
PubMed ID10358930
JournalChem Phys Lipids
Year1999
Volume98
Pages79-86
AuthorsKatada T, Kurosu H, Okada T, Suzuki T, Tsujimoto N, Takasuga S, Kontani K, Hazeki O, Ui M
TitleSynergistic activation of a family of phosphoinositide 3-kinase via G-protein coupled and tyrosine kinase-related receptors.
[25]
PubMed ID10022824
JournalEMBO J
Year1999
Volume18
Pages815-21
AuthorsJimenez JL, Guijarro JI, Orlova E, Zurdo J, Dobson CM, Sunde M, Saibil HR
TitleCryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing.
[26]
PubMed ID10212202
JournalJ Biol Chem
Year1999
Volume274
Pages12323-32
AuthorsHarpur AG, Layton MJ, Das P, Bottomley MJ, Panayotou G, Driscoll PC, Waterfield MD
TitleIntermolecular interactions of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase.
[27]
PubMed ID10356365
JournalMol Cell Biol Res Commun
Year1999
Volume1
Pages153-7
AuthorsBeeton CA, Das P, Waterfield MD, Shepherd PR
TitleThe SH3 and BH domains of the p85alpha adapter subunit play a critical role in regulating class Ia phosphoinositide 3-kinase function.
[28]
PubMed ID10358071
JournalJ Biol Chem
Year1999
Volume274
Pages17152-8
AuthorsKrugmann S, Hawkins PT, Pryer N, Braselmann S
TitleCharacterizing the interactions between the two subunits of the p101/p110gamma phosphoinositide 3-kinase and their role in the activation of this enzyme by G beta gamma subunits.
[29]
PubMed ID10580505
JournalNature
Year1999
Volume402
Pages313-20
AuthorsWalker EH, Perisic O, Ried C, Stephens L, Williams RL
TitleStructural insights into phosphoinositide 3-kinase catalysis and signalling. PDB;1qmm
[30]
PubMed ID10835283
JournalJ Mol Biol
Year2000
Volume299
Pages771-88
AuthorsKristensen SM, Siegal G, Sankar A, Driscoll PC
TitleBackbone dynamics of the C-terminal SH2 domain of the p85alpha subunit of phosphoinositide 3-kinase: effect of phosphotyrosine-peptide binding and characterization of slow conformational exchange processes.
[31]
PubMed ID10967104
JournalJ Biol Chem
Year2000
Volume275
Pages36450-6
AuthorsKing TR, Fang Y, Mahon ES, Anderson DH
TitleUsing a phage display library to identify basic residues in A-Raf required to mediate binding to the Src homology 2 domains of the p85 subunit of phosphatidylinositol 3'-kinase.
[32]
CommentsVARIANT INSULIN RESISTANCE GLN-409, AND VARIANT ILE-326
Medline ID20230645
PubMed ID10768093
JournalDiabetologia
Year2000
Volume43
Pages321-31
AuthorsBaynes KC, Beeton CA, Panayotou G, Stein R, Soos M, Hansen T, Simpson H, O'Rahilly S, Shepherd PR, Whitehead JP
TitleNatural variants of human p85 alpha phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity.
Related UniProtKBP27986
[33]
PubMed ID11123912
JournalBiochemistry
Year2000
Volume39
Pages15860-9
AuthorsWeber T, Schaffhausen B, Liu Y, Gunther UL
TitleNMR structure of the N-SH2 of the p85 subunit of phosphoinositide 3-kinase complexed to a doubly phosphorylated peptide reveals a second phosphotyrosine binding site.
[34]
PubMed ID10861385
JournalBiopolymers
Year2000
Volume57
Pages208-17
AuthorsOkishio N, Nagai M, Fukuda R, Nagatomo S, Kitagawa T
TitleInteractions of phosphatidylinositol 3-kinase Src homology 3 domain with its ligand peptide studied by absorption, circular dichroism, and UV resonance raman spectroscopies.
[35]
CommentsX-ray crystallography
PubMed ID11136978
JournalCell
Year2000
Volume103
Pages931-43
AuthorsPacold ME, Suire S, Perisic O, Lara-Gonzalez S, Davis CT, Walker EH, Hawkins PT, Stephens L, Eccleston JF, Williams RL
TitleCrystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma.
Related PDB1he8
[36]
PubMed ID11067939
JournalJ Immunol
Year2000
Volume165
Pages5798-806
AuthorsTudan C, Jackson JK, Blanis L, Pelech SL, Burt HM
TitleInhibition of TNF-alpha-induced neutrophil apoptosis by crystals of calcium pyrophosphate dihydrate is mediated by the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt pathways up-stream of caspase 3.
[37]
CommentsX-ray crystallography
PubMed ID11090628
JournalMol Cell
Year2000
Volume6
Pages909-19
AuthorsWalker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL
TitleStructural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine.
Related PDB1e7u,1e7v,1e8w,1e8x,1e8y,1e8z,1e90,1qmm
[38]
PubMed ID11418612
JournalJ Biol Chem
Year2001
Volume276
Pages36174-82
AuthorsGelkop S, Babichev Y, Isakov N
TitleT cell activation induces direct binding of the Crk adapter protein to the regulatory subunit of phosphatidylinositol 3-kinase (p85) via a complex mechanism involving the Cbl protein.
[39]
PubMed ID11567151
JournalActa Crystallogr D Biol Crystallogr
Year2001
Volume57
Pages1397-404
AuthorsPauptit RA, Dennis CA, Derbyshire DJ, Breeze AL, Weston SA, Rowsell S, Murshudov GN
TitleNMR trial models: experiences with the colicin immunity protein Im7 and the p85alpha C-terminal SH2-peptide complex.
Related PDB1h9o
[40]
PubMed ID11141062
JournalBiochemistry
Year2001
Volume40
Pages119-29
AuthorsOkishio N, Tanaka T, Fukuda R, Nagai M
TitleRole of the conserved acidic residue Asp21 in the structure of phosphatidylinositol 3-kinase Src homology 3 domain: circular dichroism and nuclear magnetic resonance studies.
[41]
PubMed ID11747457
JournalBiochemistry
Year2001
Volume40
Pages15797-804
AuthorsOkishio N, Tanaka T, Nagai M, Fukuda R, Nagatomo S, Kitagawa T
TitleIdentification of tyrosine residues involved in ligand recognition by the phosphatidylinositol 3-kinase Src homology 3 domain: circular dichroism and UV resonance Raman studies.
[42]
PubMed ID11478864
JournalJ Mol Biol
Year2001
Volume311
Pages325-40
AuthorsZurdo J, Guijarro JI, Jimenez JL, Saibil HR, Dobson CM
TitleDependence on solution conditions of aggregation and amyloid formation by an SH3 domain.
[43]
PubMed ID11401516
JournalBiochem Biophys Res Commun
Year2001
Volume282
Pages691-6
AuthorsKirsch C, Wetzker R, Klinger R
TitleAnionic phospholipids are involved in membrane targeting of PI 3-kinase gamma.
[44]
PubMed ID12367534
JournalJ Mol Biol
Year2002
Volume322
Pages1147-58
AuthorsVentura S, Lacroix E, Serrano L
TitleInsights into the origin of the tendency of the PI3-SH3 domain to form amyloid fibrils.
[45]
PubMed ID11986952
JournalLeukemia
Year2002
Volume16
Pages894-901
AuthorsJucker M, Sudel K, Horn S, Sickel M, Wegner W, Fiedler W, Feldman RA
TitleExpression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO).
[46]
PubMed ID12151228
JournalTrends Biochem Sci
Year2002
Volume27
Pages426-32
AuthorsDjordjevic S, Driscoll PC
TitleStructural insight into substrate specificity and regulatory mechanisms of phosphoinositide 3-kinases.
[47]
PubMed ID12515556
JournalBiochemistry
Year2003
Volume42
Pages208-16
AuthorsOkishio N, Tanaka T, Fukuda R, Nagai M
TitleDifferential ligand recognition by the Src and phosphatidylinositol 3-kinase Src homology 3 domains: circular dichroism and ultraviolet resonance Raman studies.
[48]
PubMed ID12629217
JournalProc Natl Acad Sci U S A
Year2003
Volume100
Pages3275-80
AuthorsFu Z, Aronoff-Spencer E, Backer JM, Gerfen GJ
TitleThe structure of the inter-SH2 domain of class IA phosphoinositide 3-kinase determined by site-directed spin labeling EPR and homology modeling.
[49]
PubMed ID15046599
JournalBiochem Soc Trans
Year2004
Volume32
Pages320-5
AuthorsKoyasu S
TitleRole of class IA phosphoinositide 3-kinase in B lymphocyte development and functions.

comments
This enzyme is composed of a catalytic subunit and a regulatory subunit.
###
The regulatory subunit of PI3-kinase, which is composed of four domains, SH3 domain, Rho-GAP domain, and two SH2 domains. The PDB structures, 1pks, 1pkt, 1pht, 1pnj, and 2pni, correspond to the SH3 domain, whilst the PDB structure, 1pbw, correspond to the Rho-GAP domain. The rest of the structures correspond to one of the two SH2 domains. The structures, 1oo3, 1oo4, 2pna and 2pnb, correspond to the first SH2 domain, whilst the structures, 1pic, 1h9o, 1bfi, 1bfj and 1qad, correspond to the second SH2 domain.
###
Although the catalytic mechanism of this enzyme is not so clear, the reaction must proceed by single displacement mechanism.
If there is no general base, the reaction mechanism must be dissociative rather than associative (see [29]). According to the literature [29] & [46], His948 might act as a general base, which would activate the acceptor hydroxyl group. However, considering the structure of the complex with ATP, Asp950, whose mutant abolishes the activity, also may act as a general base.
Moreover, this enzyme does not have a particular Lys/Arg cluster, which stabilizes the transferred phosphate group. Possibly, Lys807 may interact with the gamma-phosphate of ATP, which would be transferred to the acceptor. Lys833 and Ser806 seem to interact with alpha-phosphate and beta-phosphate, respectively.
Instead of the basic resdiues, two magnesium ions, which should be bound to Asp836, Asn951 and Asp964, must stabilize both transferred and leaving phosphate groups (gamma- and beta-phosphate groups).
Taken together, the reaction proceeds as follows:
(1) Asp950 acts as a general base to deprotonate the acceptor group of the substrate, 3-OH.
(2) The activated acceptor group makes a nuclepophilic attack on the transferred group, the gamma-phosphate of ATP, leading to the transtion-state.
(3) Lys807 may stabilize the negative charge on the transferred group, gamma-phosphate of the transition-state, along with magnesium ions. Lys833 and Ser806 seem to stabilize the leaving groups, alpha- and beta-phosphate groups, respectively. The beta-phosphate is also stabilized by the magnesium ions.
(4) Finally, the transferred group is attached to the acceptor group, with release of ADP.

createdupdated
2004-03-182009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
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Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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