|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
181 a.a.
|
|
|
|
|
|
|
|
|
|
|
22 a.a.
|
|
|
|
|
|
|
|
|
|
|
151 a.a.
|
|
|
|
|
|
|
|
|
|
|
16 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Viral protein
|
|
|
Title:
|
|
Hepatitis c protease ns3-4a serine protease with ketoamide inhibitor sch225724 bound
|
|
Structure:
|
|
Ns3 protease/helicase. Chain: a, c. Fragment: protease domain, residues 1-181. Engineered: yes. Ns4a peptide. Chain: b, d. Fragment: residues 21-39. Engineered: yes
|
|
Source:
|
|
Hepatitis c virus. Organism_taxid: 11103. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the peptide was chemically synthesized. The sequence of the protein is naturally found in hepatitis c virus type 1b.
|
|
Biol. unit:
|
|
Tetramer (from
)
|
|
Resolution:
|
|
|
2.50Å
|
R-factor:
|
0.193
|
R-free:
|
0.265
|
|
|
Authors:
|
|
A.Arasappan,F.G.Njoroge,T.Y.Chan,F.Bennett,S.L.Bogen,K.Chen, H.Gu,L.Hong,E.Jao,Y.T.Liu,R.G.Lovey,T.Parekh,R.E.Pike, P.Pinto,B.Santhanam,S.Venkatraman,H.Vaccaro,H.Wang,X.Yang, Z.Zhu,B.Mckittrick,A.K.Saksena,V.Girijavallabhan,J.Pichardo N.Butkiewicz,R.Ingram,B.Malcolm,A.J.Prongay,N.Yao,B.Marten, Madison V.,S.Kemp,O.Levy,M.Lim-Wilby,S.Tamura,A.K.Ganguly
|
|
Key ref:
|
|
A.Arasappan
et al.
(2005).
Hepatitis C virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency.
Bioorg Med Chem Lett,
15,
4180-4184.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
28-Jun-05
|
Release date:
|
04-Jul-06
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P26664
(POLG_HCV1) -
Genome polyprotein
|
|
|
|
Seq:
Struc:
|
|
|
|
3011 a.a.
181 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Q9QP61
(Q9QP61_9HEPC) -
Genome polyprotein
|
|
|
|
Seq:
Struc:
|
|
|
|
3010 a.a.
22 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class 1:
|
|
Chains A, C:
E.C.2.7.7.48
- RNA-directed Rna polymerase.
|
|
|
|
|
|
|
Reaction:
|
|
Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1)
|
|
|
|
|
|
Nucleoside triphosphate
|
+
|
RNA(n)
|
=
|
diphosphate
|
+
|
RNA(n+1)
|
|
|
|
|
|
|
|
|
|
Enzyme class 2:
|
|
Chains A, C:
E.C.3.4.21.98
- Hepacivirin.
|
|
|
|
|
|
|
Reaction:
|
|
Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1'.
|
|
|
|
|
|
Enzyme class 3:
|
|
Chains A, C:
E.C.3.6.1.15
- Nucleoside-triphosphatase.
|
|
|
|
|
|
|
Reaction:
|
|
NTP + H2O = NDP + phosphate
|
|
|
|
|
|
NTP
|
+
|
H(2)O
|
=
|
NDP
|
+
|
phosphate
|
|
|
|
|
|
|
|
|
|
Enzyme class 4:
|
|
Chains A, C:
E.C.3.6.4.13
- Rna helicase.
|
|
|
|
|
|
|
Reaction:
|
|
ATP + H2O = ADP + phosphate
|
|
|
|
|
|
ATP
|
+
|
H(2)O
|
=
|
ADP
|
+
|
phosphate
|
|
|
|
|
|
|
|
|
|
|
|
|
Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
Gene Ontology (GO) functional annotation
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Cellular component
|
virion part
|
1 term
|
|
|
Biological process
|
viral reproduction
|
3 terms
|
|
|
Biochemical function
|
catalytic activity
|
2 terms
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
Bioorg Med Chem Lett
15:4180-4184
(2005)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Hepatitis C virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency.
|
|
A.Arasappan,
F.G.Njoroge,
T.Y.Chan,
F.Bennett,
S.L.Bogen,
K.Chen,
H.Gu,
L.Hong,
E.Jao,
Y.T.Liu,
R.G.Lovey,
T.Parekh,
R.E.Pike,
P.Pinto,
B.Santhanam,
S.Venkatraman,
H.Vaccaro,
H.Wang,
X.Yang,
Z.Zhu,
B.Mckittrick,
A.K.Saksena,
V.Girijavallabhan,
J.Pichardo,
N.Butkiewicz,
R.Ingram,
B.Malcolm,
A.Prongay,
N.Yao,
B.Marten,
V.Madison,
S.Kemp,
O.Levy,
M.Lim-Wilby,
S.Tamura,
A.K.Ganguly.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
We have discovered that introduction of appropriate amino acid derivatives at
P'2 position improved the binding potency of P3-capped alpha-ketoamide
inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the
inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
K.P.Romano,
A.Ali,
W.E.Royer,
and
C.A.Schiffer
(2010).
Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding.
|
| |
Proc Natl Acad Sci U S A, 107,
20986-20991.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
M.Yi,
X.Tong,
A.Skelton,
R.Chase,
T.Chen,
A.Prongay,
S.L.Bogen,
A.K.Saksena,
F.G.Njoroge,
R.L.Veselenak,
R.B.Pyles,
N.Bourne,
B.A.Malcolm,
and
S.M.Lemon
(2006).
Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations.
|
| |
J Biol Chem, 281,
8205-8215.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
Y.M.Loo,
D.M.Owen,
K.Li,
A.K.Erickson,
C.L.Johnson,
P.M.Fish,
D.S.Carney,
T.Wang,
H.Ishida,
M.Yoneyama,
T.Fujita,
T.Saito,
W.M.Lee,
C.H.Hagedorn,
D.T.Lau,
S.A.Weinman,
S.M.Lemon,
and
M.Gale
(2006).
Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection.
|
| |
Proc Natl Acad Sci U S A, 103,
6001-6006.
|
|
|
|
|
|
The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
|
| |
Links
