1v8b
From Proteopedia
(New page: 200px<br /><applet load="1v8b" size="450" color="white" frame="true" align="right" spinBox="true" caption="1v8b, resolution 2.4Å" /> '''Crystal structure of ...) |
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| - | [[Image:1v8b.gif|left|200px]]<br /><applet load="1v8b" size=" | + | [[Image:1v8b.gif|left|200px]]<br /><applet load="1v8b" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1v8b, resolution 2.4Å" /> | caption="1v8b, resolution 2.4Å" /> | ||
'''Crystal structure of a hydrolase'''<br /> | '''Crystal structure of a hydrolase'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The human malaria parasite Plasmodium falciparum is responsible for the | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 1V8B is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum_3d7 Plasmodium falciparum 3d7] with NAD and ADN as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Adenosylhomocysteinase Adenosylhomocysteinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.1.1 3.3.1.1] Full crystallographic information is available from [http:// | + | 1V8B is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum_3d7 Plasmodium falciparum 3d7] with <scene name='pdbligand=NAD:'>NAD</scene> and <scene name='pdbligand=ADN:'>ADN</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Adenosylhomocysteinase Adenosylhomocysteinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.1.1 3.3.1.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1V8B OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Kitade, Y.]] | [[Category: Kitade, Y.]] | ||
[[Category: Kusakabe, Y.]] | [[Category: Kusakabe, Y.]] | ||
| - | [[Category: Nakamura, K | + | [[Category: Nakamura, K T.]] |
[[Category: Nakanishi, M.]] | [[Category: Nakanishi, M.]] | ||
[[Category: Shiraiwa, K.]] | [[Category: Shiraiwa, K.]] | ||
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[[Category: hydrolase]] | [[Category: hydrolase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:32:31 2008'' |
Revision as of 13:32, 21 February 2008
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Crystal structure of a hydrolase
Overview
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.
About this Structure
1V8B is a Single protein structure of sequence from Plasmodium falciparum 3d7 with and as ligands. Active as Adenosylhomocysteinase, with EC number 3.3.1.1 Full crystallographic information is available from OCA.
Reference
Crystal structure of S-adenosyl-L-homocysteine hydrolase from the human malaria parasite Plasmodium falciparum., Tanaka N, Nakanishi M, Kusakabe Y, Shiraiwa K, Yabe S, Ito Y, Kitade Y, Nakamura KT, J Mol Biol. 2004 Oct 29;343(4):1007-17. PMID:15476817
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