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PDBsum entry 3f8e
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References listed in PDB file
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Key reference
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Title
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Non-Zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors.
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Authors
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A.Maresca,
C.Temperini,
H.Vu,
N.B.Pham,
S.A.Poulsen,
A.Scozzafava,
R.J.Quinn,
C.T.Supuran.
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Ref.
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J Am Chem Soc, 2009,
131,
3057-3062.
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PubMed id
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Abstract
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The X-ray crystal structure of the adduct between the zinc metalloenzyme
carbonic anhydrase II (CA, EC 4.2.1.1) with the recently discovered natural
product coumarin derivative
6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one showed the coumarin
hydrolysis product, a cis-2-hydroxy-cinnamic acid derivative, and not the parent
coumarin, bound within the enzyme active site. The bound inhibitor exhibits an
extended, two-arm conformation that effectively plugs the entrance to the enzyme
active site with no interactions with the catalytically crucial zinc ion. The
inhibitor is sandwiched between Phe131, with which it makes an edge-to-face
stacking, and Asn67/Glu238sym, with which it makes several polar and hydrogen
bonding interactions. This unusual binding mode, with no interactions between
the inhibitor molecule and the active site metal ion is previously unobserved
for this enzyme class and presents a new opportunity for future drug design
campaigns to target a mode of inhibition that differs substantially from
classical inhibitors such as the clinically used sulfonamides and sulfamates.
Several structurally simple coumarin scaffolds were also shown to inhibit all 13
catalytically active mammalian CA isoforms, with inhibition constants ranging
from nanomolar to millimolar. The inhibition is time dependent, with maximum
inhibition being observed after 6 h.
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