1az2: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
==Overview== | ==Overview== | ||
It is generally expected that only one inhibitor molecule will bind to an, enzyme active site. In fact, specific drug design theories depend upon, this assumption. Here, we report the binding of two molecules of an, inhibitor to the same active site which we observed in the 1.8 A, resolution structure of the drug Alrestatin bound to a mutant of human, aldose reductase. The two molecules of Alrestatin bind to the active site, in a stacked arrangement (a double-decker). This stack positions the, carboxylic acid of one drug molecule near the NADP+ cofactor at a, previously determined anion binding site and the carboxylic acid of the, second drug molecule near the carboxy-terminal tail of the enzyme. We, propose that interactions of inhibitors with the carboxy-terminal loop of, aldose .. | It is generally expected that only one inhibitor molecule will bind to an, enzyme active site. In fact, specific drug design theories depend upon, this assumption. Here, we report the binding of two molecules of an, inhibitor to the same active site which we observed in the 1.8 A, resolution structure of the drug Alrestatin bound to a mutant of human, aldose reductase. The two molecules of Alrestatin bind to the active site, in a stacked arrangement (a double-decker). This stack positions the, carboxylic acid of one drug molecule near the NADP+ cofactor at a, previously determined anion binding site and the carboxylic acid of the, second drug molecule near the carboxy-terminal tail of the enzyme. We, propose that interactions of inhibitors with the carboxy-terminal loop of, aldose reductase are critical for the development of inhibitors that are, able to discriminate between aldose reductase and other members of the, aldo-keto reductase superfamily. This finding suggests a new direction for, the introduction of specificity to aldose reductase-targeted drugs. | ||
==About this Structure== | ==About this Structure== | ||
1AZ2 is a | 1AZ2 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 NAP and CIT as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] Structure known Active Site: ACT. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1AZ2 OCA]. | ||
==Reference== | ==Reference== | ||
| Line 26: | Line 26: | ||
[[Category: oxidoreductase]] | [[Category: oxidoreductase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:12:56 2007'' | ||
