 |
PDBsum entry 1gfy
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Residue 259 is a key determinant of substrate specificity of protein-Tyrosine phosphatases 1b and alpha.
|
|
|
Authors
|
|
G.H.Peters,
L.F.Iversen,
S.Branner,
H.S.Andersen,
S.B.Mortensen,
O.H.Olsen,
K.B.Moller,
N.P.Moller.
|
|
|
Ref.
|
|
J Biol Chem, 2000,
275,
18201-18209.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The aim of this study was to define the structural elements that determine the
differences in substrate recognition capacity of two protein-tyrosine
phosphatases (PTPs), PTP1B and PTPalpha, both suggested to be negative
regulators of insulin signaling. Since the Ac-DADE(pY)L-NH(2) peptide is well
recognized by PTP1B, but less efficiently by PTPalpha, it was chosen as a tool
for these analyses. Calpha regiovariation analyses and primary sequence
alignments indicate that residues 47, 48, 258, and 259 (PTP1B numbering) define
a selectivity-determining region. By analyzing a set of DADE(pY)L analogs with a
series of PTP mutants in which these four residues were exchanged between PTP1B
and PTPalpha, either in combination or alone, we here demonstrate that the key
selectivity-determining residue is 259. In PTPalpha, this residue is a glutamine
causing steric hindrance and in PTP1B a glycine allowing broad substrate
recognition. Significantly, replacing Gln(259) with a glycine almost turns
PTPalpha into a PTP1B-like enzyme. By using a novel set of PTP inhibitors and
x-ray crystallography, we further provide evidence that Gln(259) in PTPalpha
plays a dual role leading to restricted substrate recognition (directly via
steric hindrance) and reduced catalytic activity (indirectly via Gln(262)). Both
effects may indicate that PTPalpha regulates highly selective signal
transduction processes.
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. Chemical structures of compounds 1-4.
|
|
Figure 7.
Fig. 7. Schematic presentation of the catalytic reaction
showing the proposed effects of the side chain Gln259.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2000,
275,
18201-18209)
copyright 2000.
|
|
|
|
|
|
|
