1sd2: Difference between revisions
New page: left|200px<br /> <applet load="1sd2" size="450" color="white" frame="true" align="right" spinBox="true" caption="1sd2, resolution 2.1Å" /> '''STRUCTURE OF HUMAN 5... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:1sd2.gif|left|200px]]<br /> | [[Image:1sd2.gif|left|200px]]<br /><applet load="1sd2" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1sd2" size=" | |||
caption="1sd2, resolution 2.1Å" /> | caption="1sd2, resolution 2.1Å" /> | ||
'''STRUCTURE OF HUMAN 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE COMPLEXED WITH 5'-METHYLTHIOTUBERCIDIN'''<br /> | '''STRUCTURE OF HUMAN 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE COMPLEXED WITH 5'-METHYLTHIOTUBERCIDIN'''<br /> | ||
==Overview== | ==Overview== | ||
The development of new and effective antiprotozoal drugs has been a | The development of new and effective antiprotozoal drugs has been a difficult challenge because of the close similarity of the metabolic pathways between microbial and mammalian systems. 5'-Methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase is thought to be an ideal target for therapeutic drug design as the enzyme is present in many microbes but not in mammals. MTA/AdoHcy nucleosidase (MTAN) irreversibly depurinates MTA or AdoHcy to form adenine and the corresponding thioribose. The inhibition of MTAN leads to a buildup of toxic byproducts that affect various microbial pathways such as quorum sensing, biological methylation, polyamine biosynthesis, and methionine recycling. The design of nucleosidase-specific inhibitors is complicated by its structural similarity to the human MTA phosphorylase (MTAP). The crystal structures of human MTAP complexed with formycin A and 5'-methylthiotubercidin have been solved to 2.0 and 2.1 A resolution, respectively. Comparisons of the MTAP and MTAN inhibitor complexes reveal size and electrostatic potential differences in the purine, ribose, and 5'-alkylthio binding sites, which account for the substrate specificity and reactions catalyzed. In addition, the differences between the two enzymes have allowed the identification of exploitable regions that can be targeted for the development of high-affinity nucleosidase-specific inhibitors. Sequence alignments of Escherichia coli MTAN, human MTAP, and plant MTA nucleosidases also reveal potential structural changes to the 5'-alkylthio binding site that account for the substrate preference of plant MTA nucleosidases. | ||
==About this Structure== | ==About this Structure== | ||
1SD2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and MTH as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/S-methyl-5-thioadenosine_phosphorylase S-methyl-5-thioadenosine phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.28 2.4.2.28] Full crystallographic information is available from [http:// | 1SD2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=MTH:'>MTH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/S-methyl-5-thioadenosine_phosphorylase S-methyl-5-thioadenosine phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.28 2.4.2.28] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SD2 OCA]. | ||
==Reference== | ==Reference== | ||
| Line 15: | Line 14: | ||
[[Category: S-methyl-5-thioadenosine phosphorylase]] | [[Category: S-methyl-5-thioadenosine phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Cornell, K | [[Category: Cornell, K A.]] | ||
[[Category: Ealick, S | [[Category: Ealick, S E.]] | ||
[[Category: Howell, P | [[Category: Howell, P L.]] | ||
[[Category: Lee, J | [[Category: Lee, J E.]] | ||
[[Category: Riscoe, M | [[Category: Riscoe, M K.]] | ||
[[Category: Settembre, E | [[Category: Settembre, E C.]] | ||
[[Category: Sufrin, J | [[Category: Sufrin, J R.]] | ||
[[Category: MTH]] | [[Category: MTH]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
| Line 31: | Line 30: | ||
[[Category: sulfate]] | [[Category: sulfate]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:00:14 2008'' | ||
Revision as of 16:00, 21 February 2008
|
STRUCTURE OF HUMAN 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE COMPLEXED WITH 5'-METHYLTHIOTUBERCIDIN
OverviewOverview
The development of new and effective antiprotozoal drugs has been a difficult challenge because of the close similarity of the metabolic pathways between microbial and mammalian systems. 5'-Methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase is thought to be an ideal target for therapeutic drug design as the enzyme is present in many microbes but not in mammals. MTA/AdoHcy nucleosidase (MTAN) irreversibly depurinates MTA or AdoHcy to form adenine and the corresponding thioribose. The inhibition of MTAN leads to a buildup of toxic byproducts that affect various microbial pathways such as quorum sensing, biological methylation, polyamine biosynthesis, and methionine recycling. The design of nucleosidase-specific inhibitors is complicated by its structural similarity to the human MTA phosphorylase (MTAP). The crystal structures of human MTAP complexed with formycin A and 5'-methylthiotubercidin have been solved to 2.0 and 2.1 A resolution, respectively. Comparisons of the MTAP and MTAN inhibitor complexes reveal size and electrostatic potential differences in the purine, ribose, and 5'-alkylthio binding sites, which account for the substrate specificity and reactions catalyzed. In addition, the differences between the two enzymes have allowed the identification of exploitable regions that can be targeted for the development of high-affinity nucleosidase-specific inhibitors. Sequence alignments of Escherichia coli MTAN, human MTAP, and plant MTA nucleosidases also reveal potential structural changes to the 5'-alkylthio binding site that account for the substrate preference of plant MTA nucleosidases.
About this StructureAbout this Structure
1SD2 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as S-methyl-5-thioadenosine phosphorylase, with EC number 2.4.2.28 Full crystallographic information is available from OCA.
ReferenceReference
Structural comparison of MTA phosphorylase and MTA/AdoHcy nucleosidase explains substrate preferences and identifies regions exploitable for inhibitor design., Lee JE, Settembre EC, Cornell KA, Riscoe MK, Sufrin JR, Ealick SE, Howell PL, Biochemistry. 2004 May 11;43(18):5159-69. PMID:15122881
Page seeded by OCA on Thu Feb 21 15:00:14 2008