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PDBsum entry 5a6h
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References listed in PDB file
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Key reference
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Title
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An unusual natural product primary sulfonamide: synthesis, Carbonic anhydrase inhibition, And protein X-Ray structures of psammaplin c.
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Authors
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P.Mujumdar,
K.Teruya,
K.F.Tonissen,
D.Vullo,
C.T.Supuran,
T.S.Peat,
S.A.Poulsen.
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Ref.
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J Med Chem, 2016,
59,
5462-5470.
[DOI no: ]
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PubMed id
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Abstract
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Psammaplin C is one of only two described natural product primary sulfonamides.
Here we report the synthesis of psammaplin C and evaluate the inhibition profile
against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes.
The compound exhibited unprecedented inhibition of an important
cancer-associated isozyme, hCA XII, with a Ki of 0.79 nM. The compound also
displayed good isoform selectivity for hCA XII over other CAs. We present the
first reported protein X-ray crystal structures of psammaplin C in complex with
human CAs. We engineered the easily crystallized hCA II enzyme to mimic both the
hCA IX and hCA XII binding sites and then utilized protein X-ray crystallography
to determine the binding pose of psammaplin C within the hCA II, hCA IX, and hCA
XII mimic active sites, all to high resolution. This is the first time a natural
product primary sulfonamide inhibitor has been assessed for inhibition and
binding to CAs.
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