 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/inhibitor
|
PDB id
|
|
|
|
1gmy
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Hydrolase/inhibitor
|
|
|
Title:
|
|
Cathepsin b complexed with dipeptidyl nitrile inhibitor
|
|
Structure:
|
|
Cathepsin b. Chain: a, b, c. Fragment: protease domain, residues 80-333. Engineered: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
|
|
Resolution:
|
|
|
1.9Å
|
R-factor:
|
0.161
|
R-free:
|
0.199
|
|
|
Authors:
|
|
P.D.Greenspan,K.L.Clark,R.A.Tommasi,S.D.Cowen,L.W.Mcquire, D.L.Farley,J.H.Van Duzer,R.L.Goldberg,H.Zhou,Z.Du,J.J.Fitt, D.E.Coppa,Z.Fang,W.Macchia,L.Zhu,M.P.Capparelli, R.Goldstein,A.M.Wigg,J.R.Doughty,R.S.Bohacek,A.K.Knap
|
|
Key ref:
|
|
P.D.Greenspan
et al.
(2001).
Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design.
J Med Chem,
44,
4524-4534.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
25-Sep-01
|
Release date:
|
19-Sep-02
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
|
|
|
|
P07858
(CATB_HUMAN) -
Cathepsin B
|
|
|
|
Seq:
Struc:
|
|
|
|
339 a.a.
254 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.3.4.22.1
- Cathepsin B.
|
|
|
|
|
|
|
Reaction:
|
|
Hydrolysis of proteins with broad specificity for peptide bonds. Preferentially cleaves -Arg-Arg-|-Xaa bonds in small molecule substrates (thus differing from cathepsin L). In addition to being an endopeptidase, shows peptidyl-dipeptidase activity, liberating C-terminal dipeptides.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Gene Ontology (GO) functional annotation
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Biological process
|
proteolysis
|
1 term
|
|
|
Biochemical function
|
cysteine-type peptidase activity
|
2 terms
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
J Med Chem
44:4524-4534
(2001)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design.
|
|
P.D.Greenspan,
K.L.Clark,
R.A.Tommasi,
S.D.Cowen,
L.W.McQuire,
D.L.Farley,
J.H.van Duzer,
R.L.Goldberg,
H.Zhou,
Z.Du,
J.J.Fitt,
D.E.Coppa,
Z.Fang,
W.Macchia,
L.Zhu,
M.P.Capparelli,
R.Goldstein,
A.M.Wigg,
J.R.Doughty,
R.S.Bohacek,
A.K.Knap.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Cathepsin B is a member of the papain superfamily of cysteine proteases and has
been implicated in the pathology of numerous diseases, including arthritis and
cancer. As part of an effort to identify potent, reversible inhibitors of this
protease, we examined a series of dipeptidyl nitriles, starting with the
previously reported Cbz-Phe-NH-CH(2)CN (19, IC(50) = 62 microM). High-resolution
X-ray crystallographic data and molecular modeling were used to optimize the
P(1), P(2), and P(3) substituents of this template. Cathepsin B is unique in its
class in that it contains a carboxylate recognition site in the S(2)' pocket of
the active site. Inhibitor potency and selectivity were enhanced by tethering a
carboxylate functionality from the carbon alpha to the nitrile to interact with
this region of the enzyme. This resulted in the identification of compound 10, a
7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine
cathepsins.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
L.Mendieta,
A.Picó,
T.Tarragó,
M.Teixidó,
M.Castillo,
L.Rafecas,
A.Moyano,
and
E.Giralt
(2010).
Novel peptidyl aryl vinyl sulfones as highly potent and selective inhibitors of cathepsins L and B.
|
| |
ChemMedChem, 5,
1556-1567.
|
|
|
|
|
|
|
Z.Zhou,
Y.Wang,
and
S.H.Bryant
(2009).
Computational analysis of the cathepsin B inhibitors activities through LR-MMPBSA binding affinity calculation based on docked complex.
|
| |
J Comput Chem, 30,
2165-2175.
|
|
|
|
|
|
|
M.C.Myers,
A.D.Napper,
N.Motlekar,
P.P.Shah,
C.H.Chiu,
M.P.Beavers,
S.L.Diamond,
D.M.Huryn,
and
A.B.Smith
(2007).
Identification and characterization of 3-substituted pyrazolyl esters as alternate substrates for cathepsin B: the confounding effects of DTT and cysteine in biological assays.
|
| |
Bioorg Med Chem Lett, 17,
4761-4766.
|
|
|
|
|
|
|
J.Kaiser,
S.S.Kinderman,
B.C.van Esseveldt,
F.L.van Delft,
H.E.Schoemaker,
R.H.Blaauw,
and
F.P.Rutjes
(2005).
Synthetic applications of aliphatic unsaturated alpha-H-alpha-amino acids.
|
| |
Org Biomol Chem, 3,
3435-3467.
|
|
|
|
|
|
|
R.H.Law,
P.M.Smooker,
J.A.Irving,
D.Piedrafita,
R.Ponting,
N.J.Kennedy,
J.C.Whisstock,
R.N.Pike,
and
T.W.Spithill
(2003).
Cloning and expression of the major secreted cathepsin B-like protein from juvenile Fasciola hepatica and analysis of immunogenicity following liver fluke infection.
|
| |
Infect Immun, 71,
6921-6932.
|
|
|
|
|
|
|
A.A.Hernandez,
and
W.R.Roush
(2002).
Recent advances in the synthesis, design and selection of cysteine protease inhibitors.
|
| |
Curr Opin Chem Biol, 6,
459-465.
|
|
|
|
|
|
|
P.Kuhn,
K.Wilson,
M.G.Patch,
and
R.C.Stevens
(2002).
The genesis of high-throughput structure-based drug discovery using protein crystallography.
|
| |
Curr Opin Chem Biol, 6,
704-710.
|
|
|
|
|
|
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.
|
|
Links
