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PDBsum entry 5fpt
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References listed in PDB file
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Key reference
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Title
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Detection of secondary binding sites in proteins using fragment screening.
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Authors
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R.F.Ludlow,
M.L.Verdonk,
H.K.Saini,
I.J.Tickle,
H.Jhoti.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
15910-15915.
[DOI no: ]
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PubMed id
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Abstract
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Proteins need to be tightly regulated as they control biological processes in
most normal cellular functions. The precise mechanisms of regulation are rarely
completely understood but can involve binding of endogenous ligands and/or
partner proteins at specific locations on a protein that can modulate function.
Often, these additional secondary binding sites appear separate to the primary
binding site, which, for example for an enzyme, may bind a substrate. In
previous work, we have uncovered several examples in which secondary binding
sites were discovered on proteins using fragment screening approaches. In each
case, we were able to establish that the newly identified secondary binding site
was biologically relevant as it was able to modulate function by the binding of
a small molecule. In this study, we investigate how often secondary binding
sites are located on proteins by analyzing 24 protein targets for which we have
performed a fragment screen using X-ray crystallography. Our analysis shows
that, surprisingly, the majority of proteins contain secondary binding sites
based on their ability to bind fragments. Furthermore, sequence analysis of
these previously unknown sites indicate high conservation, which suggests that
they may have a biological function, perhaps via an allosteric mechanism.
Comparing the physicochemical properties of the secondary sites with known
primary ligand binding sites also shows broad similarities indicating that many
of the secondary sites may be druggable in nature with small molecules that
could provide new opportunities to modulate potential therapeutic targets.
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Secondary reference #1
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Title
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Molecular views of viral polyprotein processing revealed by the crystal structure of the hepatitis c virus bifunctional protease-Helicase.
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Authors
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N.Yao,
P.Reichert,
S.S.Taremi,
W.W.Prosise,
P.C.Weber.
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Ref.
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Structure, 1999,
7,
1353-1363.
[DOI no: ]
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PubMed id
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Figure 8.
Figure 8. HCV polyprotein processing in the nonstructural
region. Nonstructural proteins NS3, NS4A, NS4B, NS5A and NS5B
are colored purple, red, green, pink and orange, respectively.
(a) Attachment of the 1984-residue polyprotein to the membrane.
(b) NS4A activation and folding of the NS3 N terminus. (c)
Subsequent cleavage reactions. To highlight the fact that the
sequence of cleavage reactions has not been firmly established,
the N terminus of the polyprotein substrate is dotted and the
schematic diagrams are enclosed in a box. (d) The release of
NS4B and NS5A and formation of the replication complex core.
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The above figure is
reproduced from the cited reference
with permission from Cell Press
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Secondary reference #2
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Title
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Discovery of an allosteric mechanism for the regulation of hcv ns3 protein function.
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Authors
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S.M.Saalau-Bethell,
A.J.Woodhead,
G.Chessari,
M.G.Carr,
J.Coyle,
B.Graham,
S.D.Hiscock,
C.W.Murray,
P.Pathuri,
S.J.Rich,
C.J.Richardson,
P.A.Williams,
H.Jhoti.
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Ref.
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Nat Chem Biol, 2012,
8,
920-925.
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PubMed id
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