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PDBsum entry 3gpj
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Contents |
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250 a.a.
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244 a.a.
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241 a.a.
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242 a.a.
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233 a.a.
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244 a.a.
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243 a.a.
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222 a.a.
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204 a.a.
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198 a.a.
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212 a.a.
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222 a.a.
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233 a.a.
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196 a.a.
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References listed in PDB file
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Key reference
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Title
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Synthetic and structural studies on syringolin a and b reveal critical determinants of selectivity and potency of proteasome inhibition.
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Authors
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J.Clerc,
M.Groll,
D.J.Illich,
A.S.Bachmann,
R.Huber,
B.Schellenberg,
R.Dudler,
M.Kaiser.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
6507-6512.
[DOI no: ]
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PubMed id
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Abstract
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Syrbactins, a family of natural products belonging either to the syringolin or
glidobactin class, are highly potent proteasome inhibitors. Although sharing
similar structural features, they differ in their macrocyclic lactam core
structure and exocyclic side chain. These structural variations critically
influence inhibitory potency and proteasome subsite selectivity. Here, we
describe the total synthesis of syringolin A and B, which together with enzyme
kinetic and structural studies, allowed us to elucidate the structural
determinants underlying the proteasomal subsite selectivity and binding affinity
of syrbactins. These findings were used successfully in the rational design and
synthesis of a syringolin A-based lipophilic derivative, which proved to be the
most potent syrbactin-based proteasome inhibitor described so far. With a K(i)'
of 8.65 +/- 1.13 nM for the chymotryptic activity, this syringolin A derivative
displays a 100-fold higher potency than the parent compound syringolin A. In
light of the medicinal relevance of proteasome inhibitors as anticancer
compounds, the present findings may assist in the rational design and
development of syrbactin-based chemotherapeutics.
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Figure 1.
Structures of SylA (1), SylB (2), GlbA (3), and the
lipophilic SylA derivative 21.
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Figure 4.
X-ray analysis of the complex of SylB (2) and the 20S
proteasome and comparison with other syrbactins. (A) Structure
of syringolin A (1) and B (2). (B) Electrostatic potential
surface [contoured from +15 kT/e (intense blue) to −15 kT/e
(intense red)] of SylB covalently bound to β5. (C) Stereo
representation of SylB (2) bound to the chymotryptic like active
site in complex with 20S proteasome (rose, subunit β5; gray,
subunit β6). (D) Structural superimposition of SylA (1,
yellow), SylB (2, green), and GlbA (3, light gray).
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