PDBsum entry 3mhc

Lyase

PDB id: 3mhc

Contents

Protein chain

257 a.a.

Ligands

ARZ

Metals

_ZN

Waters ×229

References listed in PDB file

Key reference

• Title: Carbonic anhydrase inhibitors. The X-Ray crystal structure of human isoform ii in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors.
• Authors: B.S.Avvaru, J.M.Wagner, A.Maresca, A.Scozzafava, A.H.Robbins, C.T.Supuran, R.Mckenna.
• Ref.: Bioorg Med Chem Lett, 2010, 20, 4376-4381.
• PubMed id: 20605094

Abstract

We investigated the inhibitory activity of several 1,3,4-thiadiazole-sulfonamides against all catalytically active CA (EC 4.2.1.1), CA I-XV. The tail derivatizing the 5-position in the 1,3,4-thiadiazole-2-sulfonamide scaffold was observed to be critical as an inhibitory determinant of these compounds. The high resolution X-ray crystal structure of hCA II in complex with 5-(1-adamantylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide, showed the adamantyl moiety of the inhibitor residing in a less utilized binding pocket than that of most hydrophobic inhibitors, lined by the amino acid residues Ile91, Val121 and Phe131. This binding site may explain the diverse inhibition profiles of 5-carboxamide- and sufonamide-derivatized 1,3,4-thiadiazole-2-sulfonamides and offers a hot spot for designing isoform selective inhibitors, considering that residues 91 and 131 are highly variable among the 13 catalytically active isoforms.