2nvc: Difference between revisions
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'''Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (3)''' | {{Structure | ||
|PDB= 2nvc |SIZE=350|CAPTION= <scene name='initialview01'>2nvc</scene>, resolution 1.65Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene> and <scene name='pdbligand=ITA:{4-[(CARBOXYMETHOXY)CARBONYL]-3,3-DIOXIDO-1-OXONAPHTHO[1,2-D]ISOTHIAZOL-2(1H)-YL}ACETIC ACID'>ITA</scene> | |||
|ACTIVITY= [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] | |||
|GENE= hALR2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |||
}} | |||
'''Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (3)''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2NVC is a [ | 2NVC is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NVC OCA]. | ||
==Reference== | ==Reference== | ||
Evidence for a novel binding site conformer of aldose reductase in ligand-bound state., Steuber H, Zentgraf M, La Motta C, Sartini S, Heine A, Klebe G, J Mol Biol. 2007 May 25;369(1):186-97. Epub 2007 Mar 15. PMID:[http:// | Evidence for a novel binding site conformer of aldose reductase in ligand-bound state., Steuber H, Zentgraf M, La Motta C, Sartini S, Heine A, Klebe G, J Mol Biol. 2007 May 25;369(1):186-97. Epub 2007 Mar 15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17418233 17418233] | ||
[[Category: Aldehyde reductase]] | [[Category: Aldehyde reductase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
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[[Category: tim barrel]] | [[Category: tim barrel]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:51:41 2008'' | ||
Revision as of 18:51, 20 March 2008
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| , resolution 1.65Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Gene: | hALR2 (Homo sapiens) | ||||||
| Activity: | Aldehyde reductase, with EC number 1.1.1.21 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (3)
OverviewOverview
Human aldose reductase (ALR2) has evolved as a promising therapeutic target for the treatment of diabetic long-term complications. The binding site of this enzyme possesses two main subpockets: the catalytic anion-binding site and the hydrophobic specificity pocket. The latter can be observed in the open or closed state, depending on the bound ligand. Thus, it exhibits a pronounced capability for induced-fit adaptations, whereas the catalytic pocket exhibits rigid properties throughout all known crystal structures. Here, we determined two ALR2 crystal structures at 1.55 and 1.65 A resolution, each complexed with an inhibitor of the recently described naphtho[1,2-d]isothiazole acetic acid series. In contrast to the original design hypothesis based on the binding mode of tolrestat (1), both inhibitors leave the specificity pocket in the closed state. Unexpectedly, the more potent ligand (2) extends the catalytic pocket by opening a novel subpocket. Access to this novel subpocket is mainly attributed to the rotation of an indole moiety of Trp 20 by about 35 degrees . The newly formed subpocket provides accommodation of the naphthyl portion of the ligand. The second inhibitor, 3, differs from 2 only by an extended glycolic ester functionality added to one of its carboxylic groups. However, despite this slight structural modification, the binding mode of 3 differs dramatically from that of the first inhibitor, but provokes less pronounced induced-fit adaptations of the binding cavity. Thus, a novel binding site conformation has been identified in a region where previous complex structures suggested only low adaptability of the binding pocket. Furthermore, the two ligand complexes represent an impressive example of how the slight change of a chemically extended side-chain at a given ligand scaffold can result in a dramatically altered binding mode. In addition, our study emphasizes the importance of crystal structure analysis for the translation of affinity data into structure-activity relationships.
About this StructureAbout this Structure
2NVC is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Evidence for a novel binding site conformer of aldose reductase in ligand-bound state., Steuber H, Zentgraf M, La Motta C, Sartini S, Heine A, Klebe G, J Mol Biol. 2007 May 25;369(1):186-97. Epub 2007 Mar 15. PMID:17418233
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