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PDBsum entry 1nms
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Apoptosis, hydrolase
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PDB id
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1nms
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Contents |
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* Residue conservation analysis
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PDB id:
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Apoptosis, hydrolase
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Title:
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Caspase-3 tethered to irreversible inhibitor
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Structure:
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Caspase-3. Chain: a, b. Fragment: large subunit. Synonym: apopain. Cysteine protease cpp32. Yama protein. Cpp-32. Casp-3. Srebp cleavage activity 1. Sca-1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
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Biol. unit:
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Dimer (from
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Resolution:
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1.70Å
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R-factor:
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0.153
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R-free:
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0.183
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Authors:
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D.A.Erlanson,J.Lam,C.Wiesmann,T.N.Luong,R.L.Simmons,W.L.Delano, I.C.Choong,W.M.Flanagan,D.Lee,T.O'Brian
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Key ref:
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D.A.Erlanson
et al.
(2003).
In situ assembly of enzyme inhibitors using extended tethering.
Nat Biotechnol,
21,
308-314.
PubMed id:
DOI:
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Date:
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10-Jan-03
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Release date:
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11-Mar-03
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PROCHECK
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Headers
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References
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P42574
(CASP3_HUMAN) -
Caspase-3 from Homo sapiens
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Seq:
Struc:
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277 a.a.
240 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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DOI no:
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Nat Biotechnol
21:308-314
(2003)
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PubMed id:
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In situ assembly of enzyme inhibitors using extended tethering.
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D.A.Erlanson,
J.W.Lam,
C.Wiesmann,
T.N.Luong,
R.L.Simmons,
W.L.DeLano,
I.C.Choong,
M.T.Burdett,
W.M.Flanagan,
D.Lee,
E.M.Gordon,
T.O'Brien.
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ABSTRACT
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Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a
therapeutic target for a wide range of diseases. Using a dynamic combinatorial
technology, 'extended tethering', we identified unique nonpeptidic inhibitors
for this enzyme. Extended tethering allowed the identification of ligands that
bind to discrete regions of caspase-3 and also helped direct the assembly of
these ligands into small-molecule inhibitors. We first designed a small-molecule
'extender' that irreversibly alkylates the cysteine residue of caspase-3 and
also contains a thiol group. The modified protein was then screened against a
library of disulfide-containing small-molecule fragments. Mass-spectrometry was
used to identify ligands that bind noncovalently to the protein and that also
form a disulfide linkage with the extender. Linking the selected fragments with
binding elements from the extenders generates reversible, tight-binding
molecules that are druglike and distinct from known inhibitors. One molecule
derived from this approach inhibited apoptosis in cells.
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Selected figure(s)
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Figure 1.
Figure 1. Schematic illustration of the extended tethering
technique.
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Figure 4.
Figure 4. Evolution of selected fragments into reversible
inhibitors of caspase-3. (A) SAR of the reversible (aldehyde)
inhibitors derived from the selected fragments shown in Figure
2A. (B) Superposition of caspase-3 modified with extender A and
the salicylic acid sulfonamide tethering hit (fragment A; gray)
and caspase-3 bound to an irreversible version (in which the
aldehyde was replaced with an arylacyloxymethyl ketone) of
compound 4 (salmon). The arrow indicates a minor structural
accommodation observed in the S4 region between the tether and
the rigidified inhibitor.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Biotechnol
(2003,
21,
308-314)
copyright 2003.
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Figures were
selected
by the author.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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D.A.Erlanson,
J.W.Arndt,
M.T.Cancilla,
K.Cao,
R.A.Elling,
N.English,
J.Friedman,
S.K.Hansen,
C.Hession,
I.Joseph,
G.Kumaravel,
W.C.Lee,
K.E.Lind,
R.S.McDowell,
K.Miatkowski,
C.Nguyen,
T.B.Nguyen,
S.Park,
N.Pathan,
D.M.Penny,
M.J.Romanowski,
D.Scott,
L.Silvian,
R.L.Simmons,
B.T.Tangonan,
W.Yang,
and
L.Sun
(2011).
Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery.
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Bioorg Med Chem Lett,
21,
3078-3083.
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PDB codes:
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L.Azéma,
K.Bathany,
and
B.Rayner
(2010).
2'-O-Appended polyamines that increase triple-helix-forming oligonucleotide affinity are selected by dynamic combinatorial chemistry.
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Chembiochem,
11,
2513-2516.
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M.Drag,
and
G.S.Salvesen
(2010).
Emerging principles in protease-based drug discovery.
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Nat Rev Drug Discov,
9,
690-701.
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S.K.Mamidyala,
and
M.G.Finn
(2010).
In situ click chemistry: probing the binding landscapes of biological molecules.
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Chem Soc Rev,
39,
1252-1261.
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S.Melkko,
L.Mannocci,
C.E.Dumelin,
A.Villa,
R.Sommavilla,
Y.Zhang,
M.G.Grütter,
N.Keller,
L.Jermutus,
R.H.Jackson,
J.Scheuermann,
and
D.Neri
(2010).
Isolation of a small-molecule inhibitor of the antiapoptotic protein Bcl-xL from a DNA-encoded chemical library.
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ChemMedChem,
5,
584-590.
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D.E.Scott,
G.J.Dawes,
M.Ando,
C.Abell,
and
A.Ciulli
(2009).
A fragment-based approach to probing adenosine recognition sites by using dynamic combinatorial chemistry.
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Chembiochem,
10,
2772-2779.
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PDB codes:
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M.F.Schmidt,
and
J.Rademann
(2009).
Dynamic template-assisted strategies in fragment-based drug discovery.
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Trends Biotechnol,
27,
512-521.
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H.Ji,
B.Z.Stanton,
J.Igarashi,
H.Li,
P.Martásek,
L.J.Roman,
T.L.Poulos,
and
R.B.Silverman
(2008).
Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors.
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J Am Chem Soc,
130,
3900-3914.
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PDB codes:
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S.L.Ng,
P.Y.Yang,
K.Y.Chen,
R.Srinivasan,
and
S.Q.Yao
(2008).
"Click" synthesis of small-molecule inhibitors targeting caspases.
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Org Biomol Chem,
6,
844-847.
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C.J.Krusemark,
and
P.J.Belshaw
(2007).
Covalent labelling of fusion proteins in live cells via an engineered receptor-ligand pair.
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Org Biomol Chem,
5,
2201-2204.
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J.N.Rybak,
E.Trachsel,
J.Scheuermann,
and
D.Neri
(2007).
Ligand-Based Vascular Targeting of Disease.
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ChemMedChem,
2,
22-40.
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C.Roesli,
D.Neri,
and
J.N.Rybak
(2006).
In vivo protein biotinylation and sample preparation for the proteomic identification of organ- and disease-specific antigens accessible from the vasculature.
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Nat Protoc,
1,
192-199.
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D.A.Erlanson
(2006).
Fragment-based lead discovery: a chemical update.
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Curr Opin Biotechnol,
17,
643-652.
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G.M.Keseru,
and
G.M.Makara
(2006).
Hit discovery and hit-to-lead approaches.
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Drug Discov Today,
11,
741-748.
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P.T.Daniel,
U.Koert,
and
J.Schuppan
(2006).
Apoptolidin: induction of apoptosis by a natural product.
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Angew Chem Int Ed Engl,
45,
872-893.
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E.R.Zartler,
and
M.J.Shapiro
(2005).
Fragonomics: fragment-based drug discovery.
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Curr Opin Chem Biol,
9,
366-370.
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J.D.Cheeseman,
A.D.Corbett,
J.L.Gleason,
and
R.J.Kazlauskas
(2005).
Receptor-assisted combinatorial chemistry: thermodynamics and kinetics in drug discovery.
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Chemistry,
11,
1708-1716.
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K.F.Geoghegan,
and
M.A.Kelly
(2005).
Biochemical applications of mass spectrometry in pharmaceutical drug discovery.
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Mass Spectrom Rev,
24,
347-366.
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U.Fischer,
and
K.Schulze-Osthoff
(2005).
Apoptosis-based therapies and drug targets.
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Cell Death Differ,
12,
942-961.
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D.A.Erlanson,
J.A.Wells,
and
A.C.Braisted
(2004).
Tethering: fragment-based drug discovery.
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Annu Rev Biophys Biomol Struct,
33,
199-223.
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D.A.Erlanson,
and
S.K.Hansen
(2004).
Making drugs on proteins: site-directed ligand discovery for fragment-based lead assembly.
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Curr Opin Chem Biol,
8,
399-406.
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D.C.Rees,
M.Congreve,
C.W.Murray,
and
R.Carr
(2004).
Fragment-based lead discovery.
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Nat Rev Drug Discov,
3,
660-672.
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J.A.Hardy,
J.Lam,
J.T.Nguyen,
T.O'Brien,
and
J.A.Wells
(2004).
Discovery of an allosteric site in the caspases.
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Proc Natl Acad Sci U S A,
101,
12461-12466.
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PDB codes:
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M.Alvarado-Kristensson,
F.Melander,
K.Leandersson,
L.Rönnstrand,
C.Wernstedt,
and
T.Andersson
(2004).
p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils.
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J Exp Med,
199,
449-458.
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N.C.Meisner,
M.Hintersteiner,
V.Uhl,
T.Weidemann,
M.Schmied,
H.Gstach,
and
M.Auer
(2004).
The chemical hunt for the identification of drugable targets.
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Curr Opin Chem Biol,
8,
424-431.
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P.Alessi,
C.Ebbinghaus,
and
D.Neri
(2004).
Molecular targeting of angiogenesis.
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Biochim Biophys Acta,
1654,
39-49.
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R.Liu,
C.Y.Hsieh,
and
K.S.Lam
(2004).
New approaches in identifying drugs to inactivate oncogene products.
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Semin Cancer Biol,
14,
13-21.
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T.Berg
(2004).
Use of "tethering" for the identification of a small molecule that binds to a dynamic hot spot on the interleukin-2 surface.
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Chembiochem,
5,
1051-1053.
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V.P.Mocharla,
B.Colasson,
L.V.Lee,
S.Röper,
K.B.Sharpless,
C.H.Wong,
and
H.C.Kolb
(2004).
In situ click chemistry: enzyme-generated inhibitors of carbonic anhydrase II.
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Angew Chem Int Ed Engl,
44,
116-120.
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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.
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Links
