2o4z: Difference between revisions
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==Overview== | ==Overview== | ||
N-Hydroxysulfamide is a 2000-fold more potent inhibitor of the zinc enzyme | N-Hydroxysulfamide is a 2000-fold more potent inhibitor of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) as compared to sulfamide. It also inhibits other physiologically relevant isoforms, such as the tumor-associated CA IX and XII (K(I)s in the range of 0.865-1.34microM). In order to understand the binding of this inhibitor to the enzyme active site, the X-ray crystal structure of the human hCA II-N-hydroxysulfamide adduct was resolved. The inhibitor coordinates to the active site zinc ion by the ionized primary amino group, participating in an extended network of hydrogen bonds with amino acid residues Thr199, Thr200 and two water molecules. The additional two hydrogen bonds in which N-hydroxysulfamide bound to hCA II is involved as compared to the corresponding adduct of sulfamide may explain its higher affinity for the enzyme, also providing hints for the design of tight-binding CA inhibitors possessing an organic moiety substituting the NH group in the N-hydroxysulfamide structure. | ||
==Disease== | |||
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=611492 611492]] | |||
==About this Structure== | ==About this Structure== | ||
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==Reference== | ==Reference== | ||
Carbonic anhydrase inhibitors: | Carbonic anhydrase inhibitors: the X-ray crystal structure of the adduct of N-hydroxysulfamide with isozyme II explains why this new zinc binding function is effective in the design of potent inhibitors., Temperini C, Winum JY, Montero JL, Scozzafava A, Supuran CT, Bioorg Med Chem Lett. 2007 May 15;17(10):2795-801. Epub 2007 Feb 28. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17346964 17346964] | ||
[[Category: Carbonate dehydratase]] | [[Category: Carbonate dehydratase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Montero, J | [[Category: Montero, J L.]] | ||
[[Category: Scozzafava, a.]] | [[Category: Scozzafava, a.]] | ||
[[Category: Supuran, c | [[Category: Supuran, c t.]] | ||
[[Category: Temperini, C.]] | [[Category: Temperini, C.]] | ||
[[Category: Winum, J | [[Category: Winum, J Y.]] | ||
[[Category: HG]] | [[Category: HG]] | ||
[[Category: HSW]] | [[Category: HSW]] | ||
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[[Category: inhibitors]] | [[Category: inhibitors]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:14:28 2008'' | ||
Revision as of 19:14, 21 February 2008
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Crystal structure of the Carbonic Anhydrase II complexed with hydroxysulfamide inhibitor
OverviewOverview
N-Hydroxysulfamide is a 2000-fold more potent inhibitor of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) as compared to sulfamide. It also inhibits other physiologically relevant isoforms, such as the tumor-associated CA IX and XII (K(I)s in the range of 0.865-1.34microM). In order to understand the binding of this inhibitor to the enzyme active site, the X-ray crystal structure of the human hCA II-N-hydroxysulfamide adduct was resolved. The inhibitor coordinates to the active site zinc ion by the ionized primary amino group, participating in an extended network of hydrogen bonds with amino acid residues Thr199, Thr200 and two water molecules. The additional two hydrogen bonds in which N-hydroxysulfamide bound to hCA II is involved as compared to the corresponding adduct of sulfamide may explain its higher affinity for the enzyme, also providing hints for the design of tight-binding CA inhibitors possessing an organic moiety substituting the NH group in the N-hydroxysulfamide structure.
DiseaseDisease
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]
About this StructureAbout this Structure
2O4Z is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.
ReferenceReference
Carbonic anhydrase inhibitors: the X-ray crystal structure of the adduct of N-hydroxysulfamide with isozyme II explains why this new zinc binding function is effective in the design of potent inhibitors., Temperini C, Winum JY, Montero JL, Scozzafava A, Supuran CT, Bioorg Med Chem Lett. 2007 May 15;17(10):2795-801. Epub 2007 Feb 28. PMID:17346964
Page seeded by OCA on Thu Feb 21 18:14:28 2008