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PDBsum entry 1ydb
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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 basis of inhibitor affinity to variants of human carbonic anhydrase ii.
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Authors
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S.K.Nair,
J.F.Krebs,
D.W.Christianson,
C.A.Fierke.
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Ref.
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Biochemistry, 1995,
34,
3981-3989.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Abstract
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The activities and structures of certain L198 variants of human carbonic
anhydrase II (CAII) have been reported recently [Krebs, J. F., Rana, F., Dluhy,
R. A., & Fierke, C. A. (1993) Biochemistry 32, 4496-4505; Nair, S. K., &
Christianson, D. W. (1993) Biochemistry 32, 4506-4514]. In order to understand
the structural basis of enzyme-inhibitor affinity, we now report the
dissociation rate and equilibrium constants for acetazolamide and dansylamide
binding to 13 variants of CAII containing substituted amino acids at position
198. These data indicate that inhibitor affinity is modulated by the
hydrophobicity and charge of the 198 side chain. Furthermore, we have determined
crystal structures of L198R, L198E, and L198F CAIIs complexed with the
transition state analog acetazolamide. The substituted benzyl side chain of
L198F CAII does not occlude the substrate association pocket, and it is
therefore not surprising that this substitution has minimal effects on catalytic
properties and inhibitor binding. Nevertheless, the F198 side chain undergoes a
significant conformation change in order to accommodate the binding of
acetazolamide; the same behavior is observed for the engineered side chain of
L198R CAII. In contrast, the engineered side chain of L198E CAII does not alter
its conformation upon inhibitor binding. We conclude that the mobility and
hydrophobicity or residue 198 side chains affect enzyme-inhibitor (and
enzyme-substrate) affinity, and these structure-function relationships are
important for understanding the behavior of carbonic anhydrase isozyme III,
which bears a wild-type F198 side chain.(ABSTRACT TRUNCATED AT 250 WORDS)
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