 |
PDBsum entry 3iqh
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Design of o-Acetylserine sulfhydrylase inhibitors by mimicking nature.
|
|
|
Authors
|
|
E.Salsi,
A.S.Bayden,
F.Spyrakis,
A.Amadasi,
B.Campanini,
S.Bettati,
T.Dodatko,
P.Cozzini,
G.E.Kellogg,
P.F.Cook,
S.L.Roderick,
A.Mozzarelli.
|
|
|
Ref.
|
|
J Med Chem, 2010,
53,
345-356.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
The inhibition of cysteine biosynthesis in prokaryotes and protozoa has been
proposed to be relevant for the development of antibiotics. Haemophilus
influenzae O-acetylserine sulfhydrylase (OASS), catalyzing l-cysteine formation,
is inhibited by the insertion of the C-terminal pentapeptide (MNLNI) of serine
acetyltransferase into the active site. Four-hundred MNXXI pentapeptides were
generated in silico, docked into OASS active site using GOLD, and scored with
HINT. The terminal P5 Ile accounts for about 50% of the binding energy. Glu or
Asp at position P4 and, to a lesser extent, at position P3 also significantly
contribute to the binding interaction. The predicted affinity of 14 selected
pentapeptides correlated well with the experimentally determined dissociation
constants. The X-ray structure of three high affinity pentapeptide-OASS
complexes were compared with the docked poses. These results, combined with a
GRID analysis of the active site, allowed us to define a pharmacophoric scaffold
for the design of peptidomimetic inhibitors.
|
|
|
|
|
|
|
