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PDBsum entry 1xdn
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References listed in PDB file
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Key reference
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Title
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High resolution crystal structure of a key editosome enzyme from trypanosoma brucei: RNA editing ligase 1.
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Authors
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J.Deng,
A.Schnaufer,
R.Salavati,
K.D.Stuart,
W.G.Hol.
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Ref.
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J Mol Biol, 2004,
343,
601-613.
[DOI no: ]
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PubMed id
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Abstract
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Trypanosomatids are causative agents of several devastating tropical diseases
such as African sleeping sickness, Chagas' disease and leishmaniasis. There are
no effective vaccines available to date for treatment of these protozoan
diseases, while current drugs have limited efficacy, significant toxicity and
suffer from increasing resistance. Trypanosomatids have several remarkable and
unique metabolic and structural features that are of great interest for
developing new anti-protozoan therapeutics. One such feature is "RNA
editing", an essential process in these pathogenic protozoa. Transcripts
for key trypanosomatid mitochondrial proteins undergo extensive
post-transcriptional RNA editing by specifically inserting or deleting
uridylates from pre-mature mRNA in order to create mature mRNAs that encode
functional proteins. The RNA editing process is carried out in a approximately
1.6 MDa multi-protein complex, the editosome. In Trypanosoma brucei, one of the
editosome's core enzymes, the RNA editing ligase 1 (TbREL1), has been shown to
be essential for survival of both insect and bloodstream forms of the parasite.
We report here the crystal structure of the catalytic domain of TbREL1 at 1.2 A
resolution, in complex with ATP and magnesium. The magnesium ion interacts with
the beta and gamma-phosphate groups and is almost perfectly octahedrally
coordinated by six phosphate and water oxygen atoms. ATP makes extensive direct
and indirect interactions with the ligase via essentially all its atoms while
extending its base into a deep pocket. In addition, the ATP makes numerous
interactions with residues that are conserved in the editing ligases only.
Further away from the active site, TbREL1 contains a unique loop containing
several hydrophobic residues that are highly conserved among trypanosomatid RNA
editing ligases which may play a role in protein-protein interactions in the
editosome. The distinct characteristics of the adenine-binding pocket, and the
absence of any close homolog in the human genome, bode well for the design of
selective inhibitors that will block the essential RNA ligase function in a
number of major protozoan pathogens.
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Figure 6.
Figure 6. Superposition of TbREL1-ATP and T4Rnl2-AMP in
stereo view. The two structures are superimposed on each other
based on AMP. TbREL1 and ATP are shown in atom color and the
TbREL1 residues near the ATP binding site as labeled. T4Rnl2
(PDB id 1s68) is shown in green and the AMP is shown in cyan.
Notice the hydrogen bonding between the backbone atoms of
residues I59 and I61 in TbREL1 and the sugar moiety and
a-phosphate group of the ATP, respectively, as shown in red
broken lines; these hydrogen bonds are absent from the
T4Rnl2-AMP complex.
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Figure 7.
Figure 7. Electrostatic potential surface of TbREL1
generated by GRASP.50 Blue: positive; red: negative. ATP is
shown as ball-stick. Notice the negatively charged residue E60
near the ATP and the absence of extended positive potential
surfaces. Seven conserved trypanosomatid residues are labeled.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2004,
343,
601-613)
copyright 2004.
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