 |
PDBsum entry 2k1q
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Viral protein
|
PDB id
|
|
|
|
2k1q
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Binding of a noncovalent inhibitor exploiting the s' Region stabilizes the hepatitis c virus ns3 protease conformation in the absence of cofactor.
|
|
|
Authors
|
|
M.Gallo,
M.Pennestri,
M.J.Bottomley,
G.Barbato,
T.Eliseo,
M.Paci,
F.Narjes,
R.De francesco,
V.Summa,
U.Koch,
R.Bazzo,
D.O.Cicero.
|
|
|
Ref.
|
|
J Mol Biol, 2009,
385,
1142-1155.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
We present the first structure of a noncovalent inhibitor bound to the protease
domain of hepatitis C virus NS3 protein (NS3p), solved by NMR. The inhibitor
exploits interactions with the S' region of NS3p to form a long-lived complex,
although the absence of negative charges strongly reduces the association rate.
The inhibitor stabilizes the N-terminal domain of NS3p and the substrate-binding
site, and correctly aligns catalytic His-Asp residues. These actions were
previously attributed exclusively to the cofactor NS4A, which interacts with the
N-terminal domain of the NS3p and functions as an activator in vivo. The
structure of the inhibitor/NS3p complex is very similar to that of the NS3p-NS4A
complex, showing that binding of the NS4A cofactor is not the only event leading
to a stable active-site conformation.
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. Inhibitors of NS3–NS4A serine protease and
titration experiments. (a) Chemical structures of phenethylamide
(compound 1) and hexapeptide DEDifEChaC-OH (compound 2)
inhibitors. (b and c) Selected region of the HSQC spectra of
NS3p showing the well-resolved R123 NH signal after the addition
of different amounts of compounds 1 and 2, respectively.
|
|
Figure 2.
Fig. 2. High-resolution structure of the NS3p/compound 1
complex derived by NMR. (a) Stereoview of the superposition of
the 20 lowest-energy structures and (b) a ribbon model of the
structure. Compound 1 backbone is shown in green. Only residues
22–186 are included, since residues 1–21 are not assigned.
(c) The intermolecular interface is color-coded to indicate
electrostatic potential (negative charge: red; positive charge:
blue). (d) Schematic representations of the N-terminal domain in
the NS3–NS4A (left) and the NS3/compound 1 (right) complexes
are shown to illustrate the change in topology caused by the
insertion of the cofactor NS4A.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2009,
385,
1142-1155)
copyright 2009.
|
|
|
|
|
|
|
