ArticleThe Biochemical journal2005
Crystal structure of human carbonic anhydrase II at 1.95 A resolution in complex with 667-coumate, a novel anti-cancer agent.
Article in The Biochemical journal, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 50 citations in OpenAlex.
- Dual targeting carbonic anhydrase inhibitors as promising therapeutic approach: a structural overview.Frontiers in molecular biosciences · 2025Review
- Brain Gene Expression in a Novel Mouse Model of Postpartum Mood Disorder.Translational neuroscience · 2019Article
- Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations.Journal of enzyme inhibition and medicinal chemistry · 2017Article
- Synthesis and Anticancer Evaluation of Some New 3-Benzyl-4,8-Dimethylbenzopyrone Derivatives.The open medicinal chemistry journal · 2017Article
- Ex vivo apoptotic and autophagic influence of an estradiol analogue on platelets.Experimental hematology & oncology · 2015Article
- Kinetic and structural characterization of thermostabilized mutants of human carbonic anhydrase II.Protein engineering, design & selection : PEDS · 2012Article
- Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding.Chemical reviews · 2008Review
- A review of coumarin derivatives in pharmacotherapy of breast cancer.Current medicinal chemistry · 2008Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
CA (carbonic anhydrase) catalyses the reversible hydration of carbon dioxide into bicarbonate, and at least 14 isoforms have been identified in vertebrates. The role of CA type II in maintaining the fluid and pH balance has made it an attractive drug target for the treatment of glaucoma and cancer. 667-coumate is a potent inhibitor of the novel oncology target steroid sulphatase and is currently in Phase 1 clinical trials for hormone-dependent breast cancer. It also inhibits CA II in vitro. In the present study, CA II was crystallized with 667-coumate and the structure was determined by X-ray crystallography at 1.95 A (1 A=0.1 nm) resolution. The structure reported here is the first for an inhibitor based on a coumarin ring and shows ligation of the sulphamate group to the active-site zinc at 2.15 A through a nitrogen anion. The first two rings of the coumarin moiety are bound within the hydrophobic binding site of CA II. Important residues contributing to binding include Val-121, Phe-131, Val-135, Leu-141, Leu-198 and Pro-202. The third seven-membered ring is more mobile and is located in the channel leading to the surface of the enzyme. Pharmacokinetic studies show enhanced stability of 667-coumate in vivo and this has been ascribed to binding of CA II in erythrocytes. This result provides a structural basis for the stabilization and long half-life of 667-coumate in blood compared with its rapid disappearance in plasma, and suggests that reversible binding of inhibitors to CA may be a general method of delivering this type of labile drug.
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