6BBS

Joint X-ray/neutron structure of human carbonic anhydrase II in complex with brinzolamide

6BBS の概要

• エントリーDOI: 10.2210/pdb6bbs/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, (+)-4-ETHYLAMINO-3,4-DIHYDRO-2-(METHOXY)PROPYL-2H-THIENO[3,2-E]-1,2-THIAZINE-6-SULFONAMIDE-1,1-DIOXIDE, ... (4 entities in total)
• 機能のキーワード: drug binding, protonation state, lyase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : P00918
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29737.98

構造登録者

Kovalevsky, A.,Aggarwal, M.,McKenna, R. (登録日: 2017-10-19, 公開日: 2018-02-28, 最終更新日: 2024-03-13)

主引用文献

Kovalevsky, A.,Aggarwal, M.,Velazquez, H.,Cuneo, M.J.,Blakeley, M.P.,Weiss, K.L.,Smith, J.C.,Fisher, S.Z.,McKenna, R.
"To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation.
Structure, 26:383-390.e3, 2018

PubMed Abstract: Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX.

PubMed: 29429876
DOI: 10.1016/j.str.2018.01.006

実験手法

NEUTRON DIFFRACTION
X-RAY DIFFRACTION (2 Å)