PDBsum entry 2v1y

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protein Protein-protein interface(s) links
Transferase PDB id
Protein chains
90 a.a. *
170 a.a. *
Waters ×17
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Structure of a phosphoinositide 3-kinase alpha adaptor- binding domain (abd) in a complex with the ish2 domain from p85 alpha
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase ca subunit alpha isoform. Chain: a. Fragment: adaptor-binding domain, residues 1-108. Synonym: phosphoinositide 3-kinase p110 alpha, pi3-kinase p subunit alpha, ptdins-3-kinase p110, pi3k. Engineered: yes. Phosphatidylinositol 3-kinase regulatory subunit chain: b.
Source: Bos taurus. Bovine. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: chain a is the adaptor-binding domain from b p110 alpha. Homo sapiens. Human.
2.40Å     R-factor:   0.236     R-free:   0.292
Authors: N.Miled,Y.Yan,W.C.Hon,O.Perisic,M.Zvelebil,Y.Inbar, D.Schneidman-Duhovny,H.J.Wolfson,J.M.Backer,R.L.Williams
Key ref:
N.Miled et al. (2007). Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science, 317, 239-242. PubMed id: 17626883 DOI: 10.1126/science.1135394
30-May-07     Release date:   24-Jul-07    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P32871  (PK3CA_BOVIN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
1068 a.a.
90 a.a.
Protein chain
Pfam   ArchSchema ?
P27986  (P85A_HUMAN) -  Phosphatidylinositol 3-kinase regulatory subunit alpha
724 a.a.
170 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 2: Chain A: E.C.  - Phosphatidylinositol-4,5-bisphosphate 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

1-Phosphatidyl-myo-inositol Metabolism
      Reaction: ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
+ 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
+ 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
   Enzyme class 3: Chain A: E.C.  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ phosphoprotein
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     phosphatidylinositol 3-kinase complex   1 term 
  Biological process     phosphatidylinositol-mediated signaling   2 terms 
  Biochemical function     phosphatidylinositol 3-kinase regulator activity     1 term  


DOI no: 10.1126/science.1135394 Science 317:239-242 (2007)
PubMed id: 17626883  
Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit.
N.Miled, Y.Yan, W.C.Hon, O.Perisic, M.Zvelebil, Y.Inbar, D.Schneidman-Duhovny, H.J.Wolfson, J.M.Backer, R.L.Williams.
Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3Kalpha, with oncogenic mutations identified in both the p110alpha catalytic and the p85alpha regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110alpha domains-the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110alpha in a complex with the p85alpha inter-Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu545 to Lys545 (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.
  Selected figure(s)  
Figure 1.
Fig. 1. Structure of a class IA PI3K heterodimerization core. (A) Domain organization of PI3K catalytic (classes IA and IB) and regulatory (class IA only) subunits. N and C, N- and C-terminal lobes of the kinase domain, respectively; GAP, Rho-GAP domain. (B) Ribbon representation of ABD/iSH2 heterodimer. The three ABD residues identified as somatic mutations in colon cancers (shown in spheres) are not in the ABD/iSH2 interface. (C) The ABD has a ubiquitin-like fold. (D) A cross-section through the ABD/iSH2 interface showing the surface complementarity. (E) Underside view of the heterodimer interface showing residues that contribute substantially to the binding. C atoms of residues forming prominent interactions with the iSH2 (contributing more than nine interatomic contacts, interatomic distance < 3.8 Å) are shown as large spheres. Smaller spheres represent residues involved in less extensive interactions (four to six interatomic contacts).
Figure 4.
Fig. 4. A model showing the inhibitory contact between the nSH2 domain and the helical domain of p110 near the site of the helical domain hotspot mutations. [The p110 catalytic core was modeled on the p110 catalytic core (24).] Arg^340 and Lys^379 are part of a highly conserved phosphopeptide-binding surface on nSH2. Binding of nSH2 to the p110 helical domain and to phosphopeptide are mutually exclusive (boxed image).
  The above figures are reprinted by permission from the AAAs: Science (2007, 317, 239-242) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22898541 P.K.Vogt (2012).
Retroviral oncogenes: a historical primer.
  Nat Rev Cancer, 12, 639-648.  
21169051 A.Hoffman, A.J.Lazar, R.E.Pollock, and D.Lev (2011).
New frontiers in the treatment of liposarcoma, a therapeutically resistant malignant cohort.
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21057544 L.Song, M.Gao, W.Dong, M.Hu, J.Li, X.Shi, Y.Hao, Y.Li, and C.Huang (2011).
p85α mediates p53 K370 acetylation by p300 and regulates its promoter-specific transactivity in the cellular UVB response.
  Oncogene, 30, 1360-1371.  
21035483 L.Stephens, and P.Hawkins (2011).
Signalling via class IA PI3Ks.
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21210909 M.Hardt, N.Chantaravisoot, and F.Tamanoi (2011).
Activating mutations of TOR (target of rapamycin).
  Genes Cells, 16, 141-151.  
21035489 S.B.Gabelli, K.C.Duong-Ly, E.T.Brower, and L.M.Amzel (2011).
Capitalizing on tumor genotyping: towards the design of mutation specific inhibitors of phosphoinsitide-3-kinase.
  Adv Enzyme Regul, 51, 273-279.  
20825420 T.Mukohara (2011).
Mechanisms of resistance to anti-human epidermal growth factor receptor 2 agents in breast cancer.
  Cancer Sci, 102, 1-8.  
21362552 X.Zhang, O.Vadas, O.Perisic, K.E.Anderson, J.Clark, P.T.Hawkins, L.R.Stephens, and R.L.Williams (2011).
Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism.
  Mol Cell, 41, 567-578.
PDB code: 2y3a
20081827 A.Berndt, S.Miller, O.Williams, D.D.Le, B.T.Houseman, J.I.Pacold, F.Gorrec, W.C.Hon, Y.Liu, C.Rommel, P.Gaillard, T.Rückle, M.K.Schwarz, K.M.Shokat, J.P.Shaw, and R.L.Williams (2010).
The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
  Nat Chem Biol, 6, 117-124.
PDB codes: 2wxe 2wxf 2wxg 2wxh 2wxi 2wxj 2wxk 2wxl 2wxm 2wxn 2wxo 2wxp 2wxq 2wxr 2x38
20581867 A.Chakrabarty, B.N.Rexer, S.E.Wang, R.S.Cook, J.A.Engelman, and C.L.Arteaga (2010).
H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3.
  Oncogene, 29, 5193-5203.  
20133840 B.G.Hale, P.S.Kerry, D.Jackson, B.L.Precious, A.Gray, M.J.Killip, R.E.Randall, and R.J.Russell (2010).
Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein.
  Proc Natl Acad Sci U S A, 107, 1954-1959.
PDB code: 3l4q
20379207 B.Vanhaesebroeck, J.Guillermet-Guibert, M.Graupera, and B.Bilanges (2010).
The emerging mechanisms of isoform-specific PI3K signalling.
  Nat Rev Mol Cell Biol, 11, 329-341.  
20803067 C.M.Coughlin, D.S.Johnston, A.Strahs, M.E.Burczynski, S.Bacus, J.Hill, J.M.Feingold, C.Zacharchuk, and A.Berkenblit (2010).
Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy.
  Breast Cancer Res Treat, 124, 1.  
20378689 D.Hägerstrand, M.B.Lindh, C.Peña, C.Garcia-Echeverria, M.Nistér, F.Hofmann, and A.Ostman (2010).
PI3K/PTEN/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541.
  Neuro Oncol, 12, 967-975.  
20186503 E.Sozopoulos, H.Litsiou, G.Voutsinas, N.Mitsiades, N.Anagnostakis, T.Tseva, E.Patsouris, and S.Tseleni-Balafouta (2010).
Mutational and immunohistochemical study of the PI3K/Akt pathway in papillary thyroid carcinoma in Greece.
  Endocr Pathol, 21, 90.  
21030680 H.A.Dbouk, H.Pang, A.Fiser, and J.M.Backer (2010).
A biochemical mechanism for the oncogenic potential of the p110beta catalytic subunit of phosphoinositide 3-kinase.
  Proc Natl Acad Sci U S A, 107, 19897-19902.  
20601955 J.Barretina, B.S.Taylor, S.Banerji, A.H.Ramos, M.Lagos-Quintana, P.L.Decarolis, K.Shah, N.D.Socci, B.A.Weir, A.Ho, D.Y.Chiang, B.Reva, C.H.Mermel, G.Getz, Y.Antipin, R.Beroukhim, J.E.Major, C.Hatton, R.Nicoletti, M.Hanna, T.Sharpe, T.J.Fennell, K.Cibulskis, R.C.Onofrio, T.Saito, N.Shukla, C.Lau, S.Nelander, S.J.Silver, C.Sougnez, A.Viale, W.Winckler, R.G.Maki, L.A.Garraway, A.Lash, H.Greulich, D.E.Root, W.R.Sellers, G.K.Schwartz, C.R.Antonescu, E.S.Lander, H.E.Varmus, M.Ladanyi, C.Sander, M.Meyerson, and S.Singer (2010).
Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.
  Nat Genet, 42, 715-721.  
20085938 K.D.Courtney, R.B.Corcoran, and J.A.Engelman (2010).
The PI3K pathway as drug target in human cancer.
  J Clin Oncol, 28, 1075-1083.  
20131869 K.I.Sen, H.Wu, J.M.Backer, and G.J.Gerfen (2010).
The structure of p85ni in class IA phosphoinositide 3-kinase exhibits interdomain disorder.
  Biochemistry, 49, 2159-2166.  
20827723 K.Lasker, A.Sali, and H.J.Wolfson (2010).
Determining macromolecular assembly structures by molecular docking and fitting into an electron density map.
  Proteins, 78, 3205-3211.  
  20009532 L.Zhao, and P.K.Vogt (2010).
Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS.
  Cell Cycle, 9, 596-600.  
20713702 M.Sun, P.Hillmann, B.T.Hofmann, J.R.Hart, and P.K.Vogt (2010).
Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.
  Proc Natl Acad Sci U S A, 107, 15547-15552.  
19962457 S.B.Gabelli, D.Mandelker, O.Schmidt-Kittler, B.Vogelstein, and L.M.Amzel (2010).
Somatic mutations in PI3Kalpha: structural basis for enzyme activation and drug design.
  Biochim Biophys Acta, 1804, 533-540.  
20799872 S.Carvalho, and F.Schmitt (2010).
Potential role of PI3K inhibitors in the treatment of breast cancer.
  Future Oncol, 6, 1251-1263.  
  19634059 S.W.Park, M.R.Kang, H.S.Eom, J.Y.Han, C.H.Ahn, S.S.Kim, S.H.Lee, and N.J.Yoo (2010).
Somatic mutation of PIK3R1 gene is rare in common human cancers.
  Acta Oncol, 49, 125-127.  
20689039 Z.Sun, Z.Li, and Y.Zhang (2010).
Adult testicular dysgenesis of Inhba conditional knockout mice may also be caused by disruption of cross-talk between Leydig cells and germ cells.
  Proc Natl Acad Sci U S A, 107, E135; author reply E136.  
19962665 B.S.Jaiswal, V.Janakiraman, N.M.Kljavin, S.Chaudhuri, H.M.Stern, W.Wang, Z.Kan, H.A.Dbouk, B.A.Peters, P.Waring, T.Dela Vega, D.M.Kenski, K.K.Bowman, M.Lorenzo, H.Li, J.Wu, Z.Modrusan, J.Stinson, M.Eby, P.Yue, J.S.Kaminker, Sauvage, J.M.Backer, and S.Seshagiri (2009).
Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation.
  Cancer Cell, 16, 463-474.  
18850006 C.A.Crane, A.Panner, J.C.Murray, S.P.Wilson, H.Xu, L.Chen, J.P.Simko, F.M.Waldman, R.O.Pieper, and A.T.Parsa (2009).
PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer.
  Oncogene, 28, 306-312.  
19290933 D.A.Fruman, and G.Bismuth (2009).
Fine tuning the immune response with PI3K.
  Immunol Rev, 228, 253-272.  
19805105 D.Mandelker, S.B.Gabelli, O.Schmidt-Kittler, J.Zhu, I.Cheong, C.H.Huang, K.W.Kinzler, B.Vogelstein, and L.M.Amzel (2009).
A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane.
  Proc Natl Acad Sci U S A, 106, 16996-17001.
PDB codes: 3hhm 3hiz
19376709 E.Hirsch, L.Braccini, E.Ciraolo, F.Morello, and A.Perino (2009).
Twice upon a time: PI3K's secret double life exposed.
  Trends Biochem Sci, 34, 244-248.  
19779456 H.Lempiäinen, and T.D.Halazonetis (2009).
Emerging common themes in regulation of PIKKs and PI3Ks.
  EMBO J, 28, 3067-3073.  
19903845 H.Pang, R.Flinn, A.Patsialou, J.Wyckoff, E.T.Roussos, H.Wu, M.Pozzuto, S.Goswami, J.S.Condeelis, A.R.Bresnick, J.E.Segall, and J.M.Backer (2009).
Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA phosphoinositide 3-kinase.
  Cancer Res, 69, 8868-8876.  
19915146 H.Wu, S.C.Shekar, R.J.Flinn, M.El-Sibai, B.S.Jaiswal, K.I.Sen, V.Janakiraman, S.Seshagiri, G.J.Gerfen, M.E.Girvin, and J.M.Backer (2009).
Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants.
  Proc Natl Acad Sci U S A, 106, 20258-20263.  
19307184 I.Rodríguez-Escudero, A.Andrés-Pons, R.Pulido, M.Molina, and V.J.Cid (2009).
Phosphatidylinositol 3-kinase-dependent activation of mammalian protein kinase B/Akt in Saccharomyces cerevisiae, an in vivo model for the functional study of Akt mutations.
  J Biol Chem, 284, 13373-13383.  
19629070 J.A.Engelman (2009).
Targeting PI3K signalling in cancer: opportunities, challenges and limitations.
  Nat Rev Cancer, 9, 550-562.  
18767981 N.Chalhoub, and S.J.Baker (2009).
PTEN and the PI3-kinase pathway in cancer.
  Annu Rev Pathol, 4, 127-150.  
19644473 P.Liu, H.Cheng, T.M.Roberts, and J.J.Zhao (2009).
Targeting the phosphoinositide 3-kinase pathway in cancer.
  Nat Rev Drug Discov, 8, 627-644.  
19133120 V.Wells, and L.Mallucci (2009).
PI3K targeting by the beta-GBP cytokine negates akt gene expression and leads aggressive breast cancer cells to apoptotic death.
  Breast Cancer Res, 11, R2.  
19270693 Y.Zhong, Q.J.Wang, X.Li, Y.Yan, J.M.Backer, B.T.Chait, N.Heintz, and Z.Yue (2009).
Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex.
  Nat Cell Biol, 11, 468-476.  
17998941 A.Denley, S.Kang, U.Karst, and P.K.Vogt (2008).
Oncogenic signaling of class I PI3K isoforms.
  Oncogene, 27, 2561-2574.  
  18769153 D.A.Mordes, and D.Cortez (2008).
Activation of ATR and related PIKKs.
  Cell Cycle, 7, 2809-2812.  
18420279 E.Hirsch, E.Ciraolo, A.Ghigo, and C.Costa (2008).
Taming the PI3K team to hold inflammation and cancer at bay.
  Pharmacol Ther, 118, 192-205.  
19075596 J.P.Gustin, D.P.Cosgrove, and B.H.Park (2008).
The PIK3CA gene as a mutated target for cancer therapy.
  Curr Cancer Drug Targets, 8, 733-740.  
18633356 L.M.Amzel, C.H.Huang, D.Mandelker, C.Lengauer, S.B.Gabelli, and B.Vogelstein (2008).
Structural comparisons of class I phosphoinositide 3-kinases.
  Nat Rev Cancer, 8, 665-669.  
18268322 L.Zhao, and P.K.Vogt (2008).
Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms.
  Proc Natl Acad Sci U S A, 105, 2652-2657.  
18794883 L.Zhao, and P.K.Vogt (2008).
Class I PI3K in oncogenic cellular transformation.
  Oncogene, 27, 5486-5496.  
18285463 M.Marqués, A.Kumar, I.Cortés, A.Gonzalez-García, C.Hernández, M.C.Moreno-Ortiz, and A.C.Carrera (2008).
Phosphoinositide 3-kinases p110alpha and p110beta regulate cell cycle entry, exhibiting distinct activation kinetics in G1 phase.
  Mol Cell Biol, 28, 2803-2814.  
18216772 M.P.Wymann, and R.Schneiter (2008).
Lipid signalling in disease.
  Nat Rev Mol Cell Biol, 9, 162-176.  
18349831 N.Ahmed, C.Riley, and M.A.Quinn (2008).
An immunohistochemical perspective of PPAR beta and one of its putative targets PDK1 in normal ovaries, benign and malignant ovarian tumours.
  Br J Cancer, 98, 1415-1424.  
19010894 P.J.Eichhorn, M.Gili, M.Scaltriti, V.Serra, M.Guzman, W.Nijkamp, R.L.Beijersbergen, V.Valero, J.Seoane, R.Bernards, and J.Baselga (2008).
Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235.
  Cancer Res, 68, 9221-9230.  
18208370 S.M.Maira, C.Voliva, and C.Garcia-Echeverria (2008).
Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery.
  Expert Opin Ther Targets, 12, 223-238.  
18043260 S.Wee, C.Lengauer, and D.Wiederschain (2008).
Class IA phosphoinositide 3-kinase isoforms and human tumorigenesis: implications for cancer drug discovery and development.
  Curr Opin Oncol, 20, 77-82.  
18481344 T.Kawakami, H.Cheng, S.Hashiro, Y.Nomura, S.Tsukiji, T.Furuta, and T.Nagamune (2008).
A caged phosphopeptide-based approach for photochemical activation of kinases in living cells.
  Chembiochem, 9, 1583-1586.  
18621722 T.L.Yuan, H.S.Choi, A.Matsui, C.Benes, E.Lifshits, J.Luo, J.V.Frangioni, and L.C.Cantley (2008).
Class 1A PI3K regulates vessel integrity during development and tumorigenesis.
  Proc Natl Acad Sci U S A, 105, 9739-9744.  
18794884 T.L.Yuan, and L.C.Cantley (2008).
PI3K pathway alterations in cancer: variations on a theme.
  Oncogene, 27, 5497-5510.  
18079394 C.H.Huang, D.Mandelker, O.Schmidt-Kittler, Y.Samuels, V.E.Velculescu, K.W.Kinzler, B.Vogelstein, S.B.Gabelli, and L.M.Amzel (2007).
The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations.
  Science, 318, 1744-1748.
PDB code: 2rd0
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.