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PDBsum entry 1v8b
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References listed in PDB file
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Key reference
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Title
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Crystal structure of s-Adenosyl-L-Homocysteine hydrolase from the human malaria parasite plasmodium falciparum.
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Authors
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N.Tanaka,
M.Nakanishi,
Y.Kusakabe,
K.Shiraiwa,
S.Yabe,
Y.Ito,
Y.Kitade,
K.T.Nakamura.
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Ref.
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J Mol Biol, 2004,
343,
1007-1017.
[DOI no: ]
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PubMed id
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Abstract
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The human malaria parasite Plasmodium falciparum is responsible for the death of
more than a million people each year. The emergence of strains of malarial
parasite resistant to conventional drug therapy has stimulated searches for
antimalarials with novel modes of action. S-Adenosyl-L-homocysteine hydrolase
(SAHH) is a regulator of biological methylations. Inhibitors of SAHH affect the
methylation status of nucleic acids, proteins, and small molecules. P.falciparum
SAHH (PfSAHH) inhibitors are expected to provide a new type of chemotherapeutic
agent against malaria. Despite the pressing need to develop selective PfSAHH
inhibitors as therapeutic drugs, only the mammalian SAHH structures are
currently available. Here, we report the crystal structure of PfSAHH complexed
with the reaction product adenosine (Ado). Knowledge of the structure of the Ado
complex in combination with a structural comparison with Homo sapiens SAHH
(HsSAHH) revealed that a single substitution between the PfSAHH (Cys59) and
HsSAHH (Thr60) accounts for the differential interactions with nucleoside
inhibitors. To examine roles of the Cys59 in the interactions with nucleoside
inhibitors, a mutant PfSAHH was prepared. A replacement of Cys59 by Thr results
in mutant PfSAHH, which shows HsSAHH-like nucleoside inhibitor sensitivity. The
present structure should provide opportunities to design potent and selective
PfSAHH inhibitors.
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Figure 7.
Figure 7. Summary of the inhibitory activities of
2-functional-group-introduced noraristeromycin against HsSAHH,
PfSAHH, and mutant PfSAHH (Cys59Thr).
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Figure 8.
Figure 8. Surface representation of the active site of
PfSAHH. A molecule of 2-F-noraristeromycin (2-F-NAM) is modeled
into the Ado-binding site of PfSAHH. Superposition was done with
respect to the adenine rings of Ado and 2-F-NAM. The carbon
atoms and a fluorine atom are shown in pink and green,
respectively. A surface depression that exists specifically in
PfSAHH, but not in HsSAHH, is indicated by stars.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2004,
343,
1007-1017)
copyright 2004.
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