 |
PDBsum entry 1qad
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Crystal structure of the c-Terminal sh2 domain of the p85alpha regulatory subunit of phosphoinositide 3-Kinase: an sh2 domain mimicking its own substrate.
|
|
|
Authors
|
|
F.J.Hoedemaeker,
G.Siegal,
S.M.Roe,
P.C.Driscoll,
J.P.Abrahams.
|
|
|
Ref.
|
|
J Mol Biol, 1999,
292,
763-770.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
