3V5G

Crystal structure of human carbonic anhydrase II in complex with the 4-sulfamido-benzenesulfonamide inhibitor

Summary for 3V5G

• Entry DOI: 10.2210/pdb3v5g/pdb
• Related: 1CA2
• Descriptor: Carbonic anhydrase 2, ZINC ION, MERCURIBENZOIC ACID, ... (6 entities in total)
• Functional Keywords: 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: 30768.73

Authors

D'Ambrosio, K.,De Simone, G. (deposition date: 2011-12-16, release date: 2012-07-25, Last modification date: 2023-09-13)

Primary citation

D'Ambrosio, K.,Smaine, F.Z.,Carta, F.,De Simone, G.,Winum, J.Y.,Supuran, C.T.
Development of potent carbonic anhydrase inhibitors incorporating both sulfonamide and sulfamide groups.
J.Med.Chem., 55:6776-6783, 2012

PubMed Abstract: A series of compounds incorporating both sulfonamide and sulfamide as zinc-binding groups (ZBGs) are reported as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Crystallographic studies on the complex of hCA II with the lead compound of this series, namely, 4-sulfamido-benzenesulfonamide, revealed the binding of two molecules in the enzyme active site cavity, the first one canonically coordinated to the zinc ion by means of the sulfonamide group and the second one located at the entrance of the cavity. This observation led to the design of elongated molecules incorporating these two ZBGs, separated by a linker of proper length, to allow the simultaneous binding to these different sites. The "long" inhibitors indeed showed around 10 times better enzyme inhibitory properties as compared to the shorter molecules against four physiologically relevant human (h) isoforms, hCA I, II, IX, and XII.

PubMed: 22775345
DOI: 10.1021/jm300818k

Experimental method

X-RAY DIFFRACTION (1.5 Å)