PDBsum entry 2rd0

Transferase/oncoprotein

PDB id: 2rd0

Contents

Protein chains

997 a.a. *

139 a.a. *

* Residue conservation analysis

PDB id:

2rd0

Name:

Transferase/oncoprotein

Title:

Structure of a human p110alpha/p85alpha complex

Structure:

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform. Chain: a. Synonym: pi3-kinase p110 subunit alpha, ptdins-3- kinase p110, pi3k. Engineered: yes. Phosphatidylinositol 3-kinase regulatory subunit alpha. Chain: b. Fragment: unp residues 322-600. Synonym: pi3-kinase p85 subunit alpha, ptdins-3-kinase p85-alpha,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3ca. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: pik3r1, grb1.

Resolution:

3.05Å R-factor: 0.267 R-free: 0.323

Authors:

C.Huang,S.B.Gabelli,L.M.Amzel

Key ref:

C.H.Huang et al. (2007). The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science, 318, 1744-1748. PubMed id: 18079394 DOI: 10.1126/science.1150799

Date:

20-Sep-07 Release date: 25-Dec-07

Protein chain

P42336  (PK3CA_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform from Homo sapiens

Seq: 1068 a.a.

Struc: 997 a.a.*

Protein chain

P27986  (P85A_HUMAN) -  Phosphatidylinositol 3-kinase regulatory subunit alpha from Homo sapiens

Seq: 724 a.a.

Struc: 139 a.a.

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chain A: E.C.2.7.1.137 - phosphatidylinositol 3-kinase.
• Pathway: 1-Phosphatidyl-myo-inositol Metabolism
• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H⁺
• Enzyme class 3: Chain A: E.C.2.7.1.153 - phosphatidylinositol-4,5-bisphosphate 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate) + ADP + H⁺
• Enzyme class 4: Chain A: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 5: Chain B: E.C.?

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

reference

DOI no: 10.1126/science.1150799

Science 318:1744-1748 (2007)

PubMed id: 18079394

The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations.

C.H.Huang, D.Mandelker, O.Schmidt-Kittler, Y.Samuels, V.E.Velculescu, K.W.Kinzler, B.Vogelstein, S.B.Gabelli, L.M.Amzel.

ABSTRACT

PIK3CA, one of the two most frequently mutated oncogenes in human tumors, codes for p110alpha, the catalytic subunit of a phosphatidylinositol 3-kinase, isoform alpha (PI3Kalpha, p110alpha/p85). Here, we report a 3.0 angstrom resolution structure of a complex between p110alpha and a polypeptide containing the p110alpha-binding domains of p85alpha, a protein required for its enzymatic activity. The structure shows that many of the mutations occur at residues lying at the interfaces between p110alpha and p85alpha or between the kinase domain of p110alpha and other domains within the catalytic subunit. Disruptions of these interactions are likely to affect the regulation of kinase activity by p85 or the catalytic activity of the enzyme, respectively. In addition to providing new insights about the structure of PI3Kalpha, these results suggest specific mechanisms for the effect of oncogenic mutations in p110alpha and p85alpha.

Selected figure(s)

Figure 2.
Fig. 2. Mutations in PIK3CA identified in human cancers. (A) Distribution of representative mutations within p110 . Residues mutated in cancers are shown as CPK models. The start of the cancer-associated truncation (residue 571 of p85) is shown by the red arrowhead. (B) Electron density map of Arg^38 and Arg^88 cancer mutations shown at the interface between the ABD and the kinase domains. (C) Close-up view of the interface of the C2 domain of p110 with iSH2 of p85. The stick representation of the Asn^345 mutation of C2 and the residues within iSH2 (Asp^560 and Asn^564) with which it may interact are shown. (D) Mutations in the helical domain (Glu^542, Glu^545, and Gln^546), located at the interface with nSH2 (orange surface). (E) Mutations of the kinase domain (Met^1043 and His^1047), located near the C-terminal end of the activation loop, are shown in light green. The part of the activation loop between residues 941 and 950 could not be traced (see text).

Figure 3.
Fig. 3. Model of membrane interaction. (A) Positively charged residues on the surface of iSH2 domain of p85 (red) and loops of the C2 and kinase domains of p110 (black) are proposed to contact the negatively charged phospholipid bilayer. (B) Model of p110 /niSH2 bound to Ras and its proposed orientation with respect to the lipid membrane.

The above figures are reprinted by permission from the AAAs: Science (2007, 318, 1744-1748) copyright 2007.

Figures were selected by the author.