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PDBsum entry 2o4z
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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C.Temperini,
J.Y.Winum,
J.L.Montero,
A.Scozzafava,
C.T.Supuran.
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Ref.
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Bioorg Med Chem Lett, 2007,
17,
2795-2801.
[DOI no: ]
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PubMed id
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Abstract
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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.
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