1ZE8

Carbonic anhydrase II in complex with a membrane-impermeant sulfonamide inhibitor

Summary for 1ZE8

• Entry DOI: 10.2210/pdb1ze8/pdb
• Descriptor: Carbonic anhydrase II, ZINC ION, 4-(HYDROXYMERCURY)BENZOIC ACID, ... (6 entities in total)
• Functional Keywords: twisted beta-sheet, lyase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00918
• Total number of polymer chains: 1
• Total formula weight: 29959.49

Authors

Menchise, V.,De Simone, G.,Alterio, V.,Di Fiore, A.,Pedone, C.,Scozzafava, A.,Supuran, C.T. (deposition date: 2005-04-18, release date: 2005-10-18, Last modification date: 2024-03-13)

Primary citation

Menchise, V.,De Simone, G.,Alterio, V.,Di Fiore, A.,Pedone, C.,Scozzafava, A.,Supuran, C.T.
Carbonic anhydrase inhibitors: stacking with Phe131 determines active site binding region of inhibitors as exemplified by the X-ray crystal structure of a membrane-impermeant antitumor sulfonamide complexed with isozyme II
J.Med.Chem., 48:5721-5727, 2005

PubMed Abstract: Structure for the adduct of carbonic anhydrase II with 1-N-(4-sulfamoylphenyl-ethyl)-2,4,6-trimethylpyridinium perchlorate, a membrane-impermeant antitumor sulfonamide, is reported. The phenylethyl moiety fills the active site, making van der Waals interactions with side chains of Gln192, Val121, Phe131, Leu198, Thr200. The 2,4,6-trimethylpyridinium functionality is at van der Waals distance from the aliphatic chain of Ile91 being involved in strong offset face-to-face stacking with Phe131. Analyzing X-ray crystal structures of such adducts, two binding modes were observed: some inhibitors bind with their tail within the hydrophobic half of the active site, defined by residues Phe131, Val135, Leu198, Pro202, Leu204. Other derivatives bind with their tail in a different region, pointing toward the hydrophilic half and making strong parallel stacking with Phe131. This interaction orients the inhibitor toward the hydrophilic part of the active site. Impossibility to participate in it leads to its binding within the hydrophobic half. Such findings are relevant for designing better inhibitors targeting isozymes II, IX, and XII, some of which are overexpressed in hypoxic tumors.

PubMed: 16134940
DOI: 10.1021/jm050333c

Experimental method

X-RAY DIFFRACTION (2 Å)