3HKT

Human carbonic anhydrase II in complex with alpha-D-Glucopyranosyl-(1->4)-1-thio-beta-D-glucopyranosylsulfonamide

Summary for 3HKT

• Entry DOI: 10.2210/pdb3hkt/pdb
• Related: 3HKQ 3HKU
• Descriptor: Carbonic anhydrase 2, alpha-D-galactopyranose-(1-4)-(1S)-1,5-anhydro-1-sulfamoyl-D-galactitol, ZINC ION, ... (4 entities in total)
• Functional Keywords: carbonic anhydrase drug design, acetylation, cytoplasm, disease mutation, lyase, metal-binding, polymorphism, zinc
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 29759.85

Authors

Paul, B.,Poulsen, S.-A.,Hofmann, A. (deposition date: 2009-05-25, release date: 2009-10-13, Last modification date: 2024-03-20)

Primary citation

Lopez, M.,Paul, B.,Hofmann, A.,Morizzi, J.,Wu, Q.K.,Charman, S.A.,Innocenti, A.,Vullo, D.,Supuran, C.T.,Poulsen, S.A.
S-glycosyl primary sulfonamides--a new structural class for selective inhibition of cancer-associated carbonic anhydrases.
J.Med.Chem., 52:6421-6432, 2009

PubMed Abstract: In this paper, we present a new class of carbonic anhydrase (CA) inhibitor that was designed to selectively target the extracellular domains of the cancer-relevant CA isozymes. The aromatic moiety of the classical zinc binding sulfonamide CA inhibitors is absent from these compounds and instead they incorporate a hydrophilic mono- or disaccharide fragment directly attached to the sulfonamide group to give S-glycosyl primary sulfonamides (1-10). The inhibition properties of these compounds at the physiologically abundant human CA isozymes I and II and cancer-associated IX and XII were determined, and all compounds had moderate potency with K(i)s in the micromolar range. We present the crystal structures of anomeric sulfonamides 4, 7, and 10 and the sugar sulfamate drug topiramate in complex with human recombinant CA II. From these structures, we have obtained valuable insights into ligand-protein interactions of these novel carbohydrate-based sulfonamides with CA.

PubMed: 19827837
DOI: 10.1021/jm900914e

Experimental method

X-RAY DIFFRACTION (2.36 Å)