8OO8
Three-Dimensional Structure of Human Carbonic Anhydrase II in Complex with a Covalent Inhibitor
Summary for 8OO8
| Entry DOI | 10.2210/pdb8oo8/pdb |
| Descriptor | Carbonic anhydrase 2, ZINC ION, 3-(cyclooctylamino)-4-ethylsulfonyl-2,5,6-tris(fluoranyl)benzenesulfonamide, ... (4 entities in total) |
| Functional Keywords | ca ii, ca 2, carbonic anhydrase ii, carbonic anhydrase 2, covalent inhibitor, lyase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 29651.76 |
| Authors | Leitans, J.,Tars, K. (deposition date: 2023-04-04, release date: 2024-04-10, Last modification date: 2025-01-22) |
| Primary citation | Vaskevicius, A.,Baronas, D.,Leitans, J.,Kvietkauskaite, A.,Ruksenaite, A.,Manakova, E.,Toleikis, Z.,Kaupinis, A.,Kazaks, A.,Gedgaudas, M.,Mickeviciute, A.,Juozapaitiene, V.,Schioth, H.B.,Jaudzems, K.,Valius, M.,Tars, K.,Grazulis, S.,Meyer-Almes, F.J.,Matuliene, J.,Zubriene, A.,Dudutiene, V.,Matulis, D. Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX. Elife, 13:-, 2024 Cited by PubMed Abstract: We designed novel pre-drug compounds that transform into an active form that covalently modifies particular His residue in the active site, a difficult task to achieve, and applied to carbonic anhydrase (CAIX), a transmembrane protein, highly overexpressed in hypoxic solid tumors, important for cancer cell survival and proliferation because it acidifies tumor microenvironment helping invasion and metastases processes. The designed compounds have several functionalities: (1) primary sulfonamide group recognizing carbonic anhydrases (CA), (2) high-affinity moieties specifically recognizing CAIX among all CA isozymes, and (3) forming a covalent bond with the His64 residue. Such targeted covalent compounds possess both high initial affinity and selectivity for the disease target protein followed by complete irreversible inactivation of the protein via covalent modification. Our designed prodrug candidates bearing moderately active pre-vinylsulfone esters or weakly active carbamates optimized for mild covalent modification activity to avoid toxic non-specific modifications and selectively target CAIX. The lead inhibitors reached 2 pM affinity, the highest among known CAIX inhibitors. The strategy could be used for any disease drug target protein bearing a His residue in the vicinity of the active site. PubMed: 39688904DOI: 10.7554/eLife.101401 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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