3IBU

The crystal structure of the human carbonic anhydrase II in complex with an aliphatic sulfamate inhibitor

Summary for 3IBU

• Entry DOI: 10.2210/pdb3ibu/pdb
• Related: 1CA2 3IBI 3IBL 3IBN
• Descriptor: Carbonic anhydrase 2, ZINC ION, decyl sulfamate, ... (6 entities in total)
• Functional Keywords: carbonic anhydrase ii, protein-inhibitor complex, aliphatic sulfamate inhibitor, disease mutation, metal-binding, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00918
• Total number of polymer chains: 1
• Total formula weight: 29834.80

Authors

Alterio, V.,De Simone, G. (deposition date: 2009-07-17, release date: 2009-09-22, Last modification date: 2023-11-01)

Primary citation

Vitale, R.M.,Alterio, V.,Innocenti, A.,Winum, J.-Y.,Monti, S.M.,De Simone, G.,Supuran, C.T.
Carbonic anhydrase inhibitors. Comparison of aliphatic sulfamate/bis-sulfamate adducts with isozymes II and IX as a platform for designing tight-binding, more isoform-selective inhibitors
J.Med.Chem., 52:5990-5998, 2009

PubMed Abstract: Two approaches were used to design inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1): the tail and the ring approaches. Aliphatic sulfamates constitute a class of CA inhibitors (CAIs) that cannot be classified in either one of these categories. We report here the detailed inhibition profile of four such compounds against isoforms CAs I-XIV, the first crystallographic structures of these compounds in adduct with isoform II, and molecular modeling studies for their interaction with hCA IX. Aliphatic monosulfamates/bis-sulfamates were nanomolar inhibitors of hCAs II, IX, and XII, unlike aromatic/heterocyclic sulfonamides that promiscuously inhibit most CA isozymes with low nanomolar affinity. The bis-sulfamates incorporating 8 or 10 carbon atoms showed higher affinity for the tumor-associated hCA IX compared to hCA II, whereas the opposite was true for the monosulfamates. The explanation for their interaction with CA active site furnishes insights for obtaining compounds with increased affinity/selectivity for various isozymes.

PubMed: 19731956
DOI: 10.1021/jm900641r

Experimental method

X-RAY DIFFRACTION (1.41 Å)