 |
PDBsum entry 2ooq
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Large-Scale structural analysis of the classical human protein tyrosine phosphatome.
|
|
|
Authors
|
|
A.J.Barr,
E.Ugochukwu,
W.H.Lee,
O.N.King,
P.Filippakopoulos,
I.Alfano,
P.Savitsky,
N.A.Burgess-Brown,
S.Müller,
S.Knapp.
|
|
|
Ref.
|
|
Cell, 2009,
136,
352-363.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
Protein tyrosine phosphatases (PTPs) play a critical role in regulating cellular
functions by selectively dephosphorylating their substrates. Here we present 22
human PTP crystal structures that, together with prior structural knowledge,
enable a comprehensive analysis of the classical PTP family. Despite their
largely conserved fold, surface properties of PTPs are strikingly diverse. A
potential secondary substrate-binding pocket is frequently found in
phosphatases, and this has implications for both substrate recognition and
development of selective inhibitors. Structural comparison identified four
diverse catalytic loop (WPD) conformations and suggested a mechanism for loop
closure. Enzymatic assays revealed vast differences in PTP catalytic activity
and identified PTPD1, PTPD2, and HDPTP as catalytically inert protein
phosphatases. We propose a "head-to-toe" dimerization model for RPTPgamma/zeta
that is distinct from the "inhibitory wedge" model and that provides a molecular
basis for inhibitory regulation. This phosphatome resource gives an expanded
insight into intrafamily PTP diversity, catalytic activity, substrate
recognition, and autoregulatory self-association.
|
|
|
|
|
|
|
|
Figure 3.
Figure 3. Novel Conformations and Movement of the Catalytic
(WPD) Loop
(A) WPD loop conformations are shown by a PTP
representative of each state: closed (blue, PTP1B, PDB: 1SUG);
open (yellow, PTP1B, PDB: 2HNP); and atypical (magenta, GLEPP1,
PDB: 2GJT; STEP, PDB: 2BIJ; Lyp, PDB: 2P6X). The intermediate
WPD loop conformation of PCPTP1 (PDB: 2A8B) is not shown for
clarity. Other PTP structures are shown with a thin transparent
line tracing the backbone and are colored according to
conformation.
(B) Superimposition of the structure of
STEP-C/S in complex with pY (PDB: 2CJZ; gray) and the apo STEP
(PDB: 2BIJ; light green) showing that the WPD loop conformation
does not change on substrate binding (pTyr, orange). The
catalytic water molecule (Wa) corresponding to that found in
closed structures is shown.
(C) Superimposition of the
structure of STEP-C/S in complex with pY (PDB: 2CJZ; green) and
PTP1B with the insulin receptor peptide (PDB: 1G1H; red). The
conserved water molecule found in closed structures is shown:
PTP1B (1SUG, yellow); GLEPP1 (2G59, orange); HePTP (2A3K,
black), DEP1 (2NZ6, magenta). The arrow indicates the position
of the displaced water molecule in STEP-C/S structure.
|
|
Figure 4.
Figure 4. Secondary Substrate-Binding Pockets
(A) Two
extreme conformations of the second-site loop are shown (orange)
from RPTPγ (extended helix) and HEPTP (closed in conformation).
The catalytic cysteine is shown in a space-filling CPK
representation, and loops are colored as follows: WPD (magenta),
β5/β6 loop (green), and gateway (red). The dually pTyr
phosphorylated insulin receptor peptide (from PDB: 1G1H) is
shown superimposed (for reference only) to indicate the position
of the secondary substrate-binding pocket. The positions of
Arg24 and gateway residues Met258 and Gly259 of PTP1B are shown
in an enlarged view.
(B) Surface topology and electrostatic
charge for the active site (pY), gateway region, and secondary
pocket (2pY) are shown for each of the five categories with the
dually pTyr phosphorylated insulin receptor peptide
superimposed.
(C) Representative second-site loop
conformations are shown for each category (see also Supplemental
Data). Category I: SHP2, BDP1, LYP; Category II: IA2, IA2β;
Category III: LAR, RPTPσ; Category IV: PTPH1, MEG1, PTPD2,
CD45; Category V: STEP, HEPTP, PCPTP1.
|
|
|
|
|
|
The above figures are
reprinted
from an Open Access publication published by Cell Press:
Cell
(2009,
136,
352-363)
copyright 2009.
|
|
|
|
|
|
|
