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PDBsum entry 5gmm
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References listed in PDB file
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Key reference
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Title
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Structural insight into the inhibition of carbonic anhydrase by the cox-2-Selective inhibitor polmacoxib (cg100649).
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Authors
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H.T.Kim,
H.Cha,
K.Y.Hwang.
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Ref.
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Biochem Biophys Res Commun, 2016,
478,
1-6.
[DOI no: ]
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PubMed id
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Abstract
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Polmacoxib is not only a selective COX-2 inhibitor but also a potent inhibitor
of carbonic anhydrases (CAs). Both CA I and CA II are highly expressed in the GI
tract and kidneys, organs that are also thought to be the sites at which
selective COX-2 inhibitors show their side effects. By inhibition assays, we
show that both CA I and CA II are strongly inhibited by polmacoxib, while CA II
also demonstrates direct competition with COX-2. To understand, at the molecular
level, how polmacoxib interacts with CA I and II, we solved the first crystal
structures of CA I and CA II in complex with polmacoxib, at 2.0 Å and 1.8 Å,
respectively. Interestingly, three polmacoxib molecules bind to the active site
of CA I, whereas only one molecule binds CA II. In the active site, the three
molecules of polmacoxib organize itself along hydrophobic interaction as
"stack-on-formation", and fully occupy a cone-shaped active pocket in
CA I. The binding mode of polmacoxib to CA II was found different than its
binding to celecoxib and valdecoxib. Our results provide structural insight into
inhibition of CA I and CA II by polmacoxib, to assess its potential clinical
efficacy.
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