ArticleProceedings of the National Academy of Sciences of the United States of America2009
Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 147 papers.
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147 citing papers in PubMed, 514 citations in OpenAlex.
- Real-Time Binding Kinetics of Small Molecules to CA IX in Live Suspension Cells Using SPR Microscopy.ACS medicinal chemistry letters · 2026Article
- Carbonic Anhydrase Inhibitors in Oncology.Sub-cellular biochemistry · 2026Review
- Computational Approaches and Structure-Based Drug Design of CAIs.Sub-cellular biochemistry · 2026Review
- Multi-faceted exploration of the novel active γ-carbonic anhydrase PaCAγ1 in the human pathogen Pseudomonas aeruginosa.International journal of biological macromolecules · 2025Article
- Computational Discovery of Selective Carbonic Anhydrase IX (CA IX) Inhibitors via Pharmacophore Modeling and Molecular Simulations for Cancer Therapy.International journal of molecular sciences · 2025Article
- Design, synthesis, molecular modelling investigation and biological studies of novel human carbonic anhydrase inhibitors based on coumalic acid.RSC medicinal chemistry · 2025Article
- Selective Inhibition of Carbonic Anhydrase IX and XII by Natural Coumarin Coladonin and Its Derivatives: Promising Antimelanoma and Antiglioblastoma Agents.ACS medicinal chemistry letters · 2025Article
- Review
- Synthesis and Evaluation of Thiazolidinone-Isatin Hybrids for Selective Inhibition of Cancer-Related Carbonic Anhydrases.ACS medicinal chemistry letters · 2025Article
- Investigation on Human Carbonic Anhydrase IX and XII Inhibitory Activity and A549 Antiproliferative Activity of a New Class of Coumarinamides.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Article
- The carbonic anhydrase enzymes as new targets for the management of neglected tropical diseases.Archiv der Pharmazie · 2025Review
- Article
- Targeting CA9 restricts pancreatic cancer progression through pH regulation and ROS production.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- Hydrogen Sulfide-Releasing Carbonic Anhydrase Inhibitors Effectively Suppress Cancer Cell Growth.International journal of molecular sciences · 2024Article
- Design and synthesis of chromene-1,2,3-triazole benzene sulfonamide hybrids as potent carbonic anhydrase-IX inhibitors against prostate cancer.RSC medicinal chemistry · 2024Article
- Crystal Structure, Theoretical Analysis, and Protein/DNA Binding Activity of Iron(III) Complex Containing Differently Protonated Pyridoxal-International journal of molecular sciences · 2024Article
- New sulfonamide-based glycosides incorporated 1,2,3-triazole as cytotoxic agents through VEGFR-2 and carbonic anhydrase inhibitory activity.Scientific reports · 2024Article
- Review
- Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects.Molecular cancer · 2024Article
87 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Carbonic anhydrase (CA) IX is a plasma membrane-associated member of the alpha-CA enzyme family, which is involved in solid tumor acidification. It is a marker of tumor hypoxia and a prognostic factor in several human cancers. An aberrant increase in CA IX expression in chronic hypoxia and during development of various carcinomas contributes to tumorigenesis through at least two mechanisms: pH regulation and cell adhesion control. Here we report the X-ray structure of the catalytic domain of CA IX in complex with a classical, clinically used sulfonamide inhibitor, acetazolamide. The structure reveals a typical alpha-CA fold, which significantly differs from the other CA isozymes when the protein quaternary structure is considered. Thus, two catalytic domains of CA IX associate to form a dimer, which is stabilized by the formation of an intermolecular disulfide bond. The active site clefts and the PG domains are located on one face of the dimer, while the C-termini are located on the opposite face to facilitate protein anchoring to the cell membrane. A correlation between the three-dimensional structure and the physiological role of the enzyme is here suggested, based on the measurement of the pH profile of the catalytic activity for the physiological reaction, CO(2) hydration to bicarbonate and protons. On the basis of the structural differences observed between CA IX and the other membrane-associated alpha-CAs, further prospects for the rational drug design of isozyme-specific CA inhibitors are proposed, given that inhibition of this enzyme shows antitumor activity both in vitro and in vivo.
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