9FLF

Three-Dimensional Structure of Human Carbonic Anhydrase IX in Complex with a Covalent Inhibitor

これはPDB形式変換不可エントリーです。

9FLF の概要

• エントリーDOI: 10.2210/pdb9flf/pdb
• 分子名称: Carbonic anhydrase, ZINC ION, 3-[[(1~{R},4~{Z})-cyclododec-4-en-1-yl]amino]-4-ethylsulfonyl-2,5,6-tris(fluoranyl)benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: ca ix, ca 9, carbonic anhydrase ix, carbonic anhydrase 9, covalent inhibitor, lyase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 114550.35

構造登録者

Leitans, J.,Tars, K. (登録日: 2024-06-05, 公開日: 2024-12-18, 最終更新日: 2025-01-22)

主引用文献

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

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: 39688904
DOI: 10.7554/eLife.101401

実験手法

X-RAY DIFFRACTION (2.2 Å)