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High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design.


ABSTRACT: The crystal structure of human carbonic anhydrase II (CA II) complexed with the inhibitor acetazolamide (AZM) has been determined at 1.1 A resolution and refined to an R(cryst) of 11.2% and an R(free) of 14.7%. As observed in previous CA II-inhibitor complexes, AZM binds directly to the zinc and makes several key interactions with active-site residues. The high-resolution data also showed a glycerol molecule adjacent to the AZM in the active site and two additional AZMs that are adventitiously bound on the surface of the enzyme. The co-binding of AZM and glycerol in the active site demonstrate that given an appropriate ring orientation and substituents, an isozyme-specific CA inhibitor may be developed.

SUBMITTER: Sippel KH 

PROVIDER: S-EPMC2765883 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design.

Sippel Katherine H KH   Robbins Arthur H AH   Domsic John J   Genis Caroli C   Agbandje-McKenna Mavis M   McKenna Robert R  

Acta crystallographica. Section F, Structural biology and crystallization communications 20090925 Pt 10


The crystal structure of human carbonic anhydrase II (CA II) complexed with the inhibitor acetazolamide (AZM) has been determined at 1.1 A resolution and refined to an R(cryst) of 11.2% and an R(free) of 14.7%. As observed in previous CA II-inhibitor complexes, AZM binds directly to the zinc and makes several key interactions with active-site residues. The high-resolution data also showed a glycerol molecule adjacent to the AZM in the active site and two additional AZMs that are adventitiously b  ...[more]

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