PDBsum entry 1qad

Transferase

PDB id: 1qad

Contents

Protein chain

104 a.a. *

Waters ×185

* Residue conservation analysis

PDB id:

1qad

Name:

Transferase

Title:

Crystal structure of thE C-terminal sh2 domain of the p85 alpha regulatory subunit of phosphoinositide 3-kinase: an sh2 domain mimicking its own substrate

Structure:

Pi3-kinase p85 alpha subunit. Chain: a. Fragment: c-terminal sh2 domain. Engineered: yes

Source:

Bos taurus. Cattle. Organism_taxid: 9913.

Resolution:

1.80Å R-factor: 0.158 R-free: 0.236

Authors:

P.J.Hoedemaeker,G.Siegal,M.Roe,P.C.Driscoll,J.P.A.Abrahams

Key ref:

F.J.Hoedemaeker et al. (1999). Crystal structure of the C-terminal SH2 domain of the p85alpha regulatory subunit of phosphoinositide 3-kinase: an SH2 domain mimicking its own substrate. J Mol Biol, 292, 763-770. PubMed id: 10525402 DOI: 10.1006/jmbi.1999.3111

Date:

26-Feb-99 Release date: 27-Oct-99

Protein chain

P23727  (P85A_BOVIN) -  Phosphatidylinositol 3-kinase regulatory subunit alpha from Bos taurus

Seq: 724 a.a.

Struc: 104 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1006/jmbi.1999.3111

J Mol Biol 292:763-770 (1999)

PubMed id: 10525402

Crystal structure of the C-terminal SH2 domain of the p85alpha regulatory subunit of phosphoinositide 3-kinase: an SH2 domain mimicking its own substrate.

F.J.Hoedemaeker, G.Siegal, S.M.Roe, P.C.Driscoll, J.P.Abrahams.

ABSTRACT

The binding properties of Src homology-2 (SH2) domains to phosphotyrosine (pY)-containing peptides have been studied in recent years with the elucidation of a large number of crystal and solution structures. Taken together, these structures suggest a general mode of binding of pY-containing peptides, explain the specificities of different SH2 domains, and may be used to design inhibitors of pY binding by SH2 domain-containing proteins. We now report the crystal structure to 1.8 A resolution of the C-terminal SH2 domain (C-SH2) of the P85alpha regulatory subunit of phosphoinositide 3-kinase (PI3 K). Surprisingly, the carboxylate group of Asp2 from a neighbouring molecule occupies the phosphotyrosine binding site and interacts with Arg18 (alphaA2) and Arg36 (betaB5), in a similar manner to the phosphotyrosine-protein interactions seen in structures of other SH2 domains complexed with pY peptides. It is the first example of a non-phosphate-containing, non-aromatic mimetic of phosphotyrosine binding to SH2 domains, and this could have implications for the design of substrate analogues and inhibitors. Overall, the crystal structure closely resembles the solution structure, but a number of loops which demonstrate mobility in solution are well defined by the crystal packing. C-SH2 has adopted a binding conformation reminiscent of the ligand bound N-terminal SH2 domain of PI3K, apparently induced by the substrate mimicking of a neighbouring molecule in the crystal.

Selected figure(s)

Figure 2.
Figure 2. Ribbon diagram of the crystal structure of C-SH2. The various structural elements are labelled using the nomenclature described by [Eck et al 1993]. The disordered BC loop (residues 39-42) is indicated with a broken line.

Figure 3.
Figure 3. Stereo image of the superposition of the ensemble of NMR conformers and the crystal structure of C-SH2. The backbone of the crystal structure is shown in red, while that of the NMR conformers is shown in blue. The N and C termini are marked. The disordered BC loop (residues 39-42) is replaced by a pseudobond between C' of residue 38 and N of residue 43. The superposition was based on the backbone atoms of residues 11-14, 19-24, 32-37, 43-50, 53-59, 78-86, 103-105.

The above figures are reprinted by permission from Elsevier: J Mol Biol (1999, 292, 763-770) copyright 1999.

Figures were selected by an automated process.