 |
PDBsum entry 2i4h
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Engineering the catalytic domain of human protein tyrosine phosphatase beta for structure-Based drug discovery.
|
|
|
Authors
|
|
A.G.Evdokimov,
M.Pokross,
R.Walter,
M.Mekel,
B.Cox,
C.Li,
R.Bechard,
F.Genbauffe,
R.Andrews,
C.Diven,
B.Howard,
V.Rastogi,
J.Gray,
M.Maier,
K.G.Peters.
|
|
|
Ref.
|
|
Acta Crystallogr D Biol Crystallogr, 2006,
62,
1435-1445.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Protein tyrosine phosphatases (PTPs) play roles in many biological processes and
are considered to be important targets for drug discovery. As inhibitor
development has proven challenging, crystal structure-based design will be very
helpful to advance inhibitor potency and selectivity. Successful application of
protein crystallography to drug discovery heavily relies on high-quality crystal
structures of the protein of interest complexed with pharmaceutically
interesting ligands. It is very important to be able to produce protein-ligand
crystals rapidly and reproducibly for as many ligands as necessary. This study
details our efforts to engineer the catalytic domain of human protein tyrosine
phosphatase beta (HPTPbeta-CD) with properties suitable for rapid-turnaround
crystallography. Structures of apo HPTPbeta-CD and its complexes with several
novel small-molecule inhibitors are presented here for the first time.
|
|
|
|
|
|
|
|
Figure 3.
Figure 3 Detailed view of the PTP  -CD
active site. (a) Hydrogen-bonding network (blue dashes) bridging
the ligand (vanadate ion, balls-and-stick representation) and
the protein (sticks). (b) Side view depicting additional
interactions (magenta dashes) between the ligand and polar
residues in the active site. The partial covalent bond between
Cys1904 and the V atom is shown as an orange dashed line. (c)
Side view of a pTyr mimetic (p-ethyl phenylsulfamic acid) bound
in the active site of the enzyme. Relevant hydrogen bonds are
shown as colored dashes.
|
|
Figure 4.
Figure 4 Transition of the WPD-loop between open (light brown)
and closed (green) states. The ligand (sulfamic acid, yellow) is
shown in ball-and-stick representation and relevant protein
residues are shown as sticks colored according to the loop
state. The catalytically important water molecule is shown as a
red sphere.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2006,
62,
1435-1445)
copyright 2006.
|
|
|
|
|
|
|
