3MHC

Crystal structure of human cabonic anhydrase II in adduct with an adamantyl analogue of acetazolamide in a novel hydrophobic binding pocket

Summary for 3MHC

• Entry DOI: 10.2210/pdb3mhc/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, (3S,5S,7S)-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)tricyclo[3.3.1.1~3,7~]decane-1-carboxamide, ... (4 entities in total)
• Functional Keywords: carbonic anhydrase inhibitors, adamantyl, acetazolamide, lyase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00918
• Total number of polymer chains: 1
• Total formula weight: 29696.91

Authors

Avvaru, B.S. (deposition date: 2010-04-07, release date: 2010-07-21, Last modification date: 2023-09-06)

Primary citation

Avvaru, B.S.,Wagner, J.M.,Maresca, A.,Scozzafava, A.,Robbins, A.H.,Supuran, C.T.,McKenna, R.
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.
Bioorg.Med.Chem.Lett., 20:4376-4381, 2010

PubMed 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.

PubMed: 20605094
DOI: 10.1016/j.bmcl.2010.06.082

Experimental method

X-RAY DIFFRACTION (1.698 Å)