An inhibitor-like binding mode of a carbonic anhydrase activator within the active site of isoform II.

Abstract:

:The 2,4,6-trimethylpyridinium derivative of histamine is an effective activator of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). However, unlike other CA activators, which bind at the entrance of the active site cavity, an X-ray crystal structure of hCA II in complex with the 1-[2-(1H-imidazol-4-yl)-ethyl]-2,4,6-trimethylpyridinium salt evidenced a binding mode never observed before either for activators or inhibitors of this enzyme, with the 2,4,6-trimethylpyridinium ring pointing towards the metal ion deep within the enzyme cavity, and several strong hydrophobic interactions stabilizing the adduct. Indeed, incubation of the activator with the enzyme for several days leads to potent inhibitory effects. This is the first example of a CA activator which after a longer contact with the enzyme behaves as an inhibitor.

journal_name

Bioorg Med Chem Lett

authors

Dave K,Ilies MA,Scozzafava A,Temperini C,Vullo D,Supuran CT

doi

10.1016/j.bmcl.2010.10.045

subject

Has Abstract

pub_date

2011-05-01 00:00:00

pages

2764-8

issue

9

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(10)01496-4

journal_volume

21

pub_type

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