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PDBsum entry 2etl
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Hydrolase, ligase
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PDB id
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2etl
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References listed in PDB file
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Key reference
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Title
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Structural basis for conformational plasticity of the parkinson'S disease-Associated ubiquitin hydrolase uch-L1.
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Authors
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C.Das,
Q.Q.Hoang,
C.A.Kreinbring,
S.J.Luchansky,
R.K.Meray,
S.S.Ray,
P.T.Lansbury,
D.Ringe,
G.A.Petsko.
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Ref.
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Proc Natl Acad Sci U S A, 2006,
103,
4675-4680.
[DOI no: ]
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PubMed id
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Abstract
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The ubiquitin C-terminal hydrolase UCH-L1 (PGP9.5) comprises >1% of total brain
protein but is almost absent from other tissues [Wilkinson, K. D., et al. (1989)
Science 246, 670-673]. Mutations in the UCH-L1 gene have been reported to be
linked to susceptibility to and protection from Parkinson's disease [Leroy, E.,
et al. (1998) Nature 395, 451-452; Maraganore, D. M., et al. (1999) Neurology
53, 1858-1860]. Abnormal overexpression of UCH-L1 has been shown to correlate
with several forms of cancer [Hibi, K., et al. (1998) Cancer Res. 58,
5690-5694]. Because the amino acid sequence of UCH-L1 is similar to that of
other ubiquitin C-terminal hydrolases, including the ubiquitously expressed
UCH-L3, which appear to be unconnected to neurodegenerative disease, the
structure of UCH-L1 and the effects of disease associated mutations on the
structure and function are of considerable importance. We have determined the
three-dimensional structure of human UCH-L1 at 2.4-A resolution by x-ray
crystallography. The overall fold resembles that of other ubiquitin hydrolases,
including UCH-L3, but there are a number of significant differences. In
particular, the geometry of the catalytic residues in the active site of UCH-L1
is distorted in such a way that the hydrolytic activity would appear to be
impossible without substrate induced conformational rearrangements.
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Figure 3.
Fig. 3. Molecular surface of UCH-L1. Conserved acidic side
chains are colored red, basic side chains are colored blue,
polar side chains are colored orange, and all nonconserved
residues according to Fig. 1 are colored gray. B is related to A
by a rotation of 50° about the y axis. D is related to C by
a rotation of 90° about the x axis.
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Figure 4.
Fig. 4. Structure of UCH-L1's active site. Backbone atoms
are presented as semitransparent orange ribbons. Atoms of
interest are presented as sticks and spheres. Oxygens, red;
nitrogen, blue; sulfur, gold; chlorine, green. Distances between
two atoms are presented with gray dashed lines. Electron density
(contoured at 1.5  ) is shown as gray
lines.
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