6US9

Influenza A M2 proton channel wild type TM domain bound to R-rimantadine

6US9 の概要

• エントリーDOI: 10.2210/pdb6us9/pdb
• 分子名称: Matrix protein 2, RIMANTADINE, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: proton channel, rimantadine, membrane protein
• 由来する生物種: Influenza A virus (A/Jinfang/132/2002(H3N2))
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 44928.46

構造登録者

Thomaston, J.L.,DeGrado, W.F. (登録日: 2019-10-25, 公開日: 2020-10-28, 最終更新日: 2024-10-09)

主引用文献

Thomaston, J.L.,Samways, M.L.,Konstantinidi, A.,Ma, C.,Hu, Y.,Bruce Macdonald, H.E.,Wang, J.,Essex, J.W.,DeGrado, W.F.,Kolocouris, A.
Rimantadine Binds to and Inhibits the Influenza A M2 Proton Channel without Enantiomeric Specificity.
Biochemistry, 2021

PubMed Abstract: The influenza A M2 wild-type (WT) proton channel is the target of the anti-influenza drug rimantadine. Rimantadine has two enantiomers, though most investigations into drug binding and inhibition have used a racemic mixture. Solid-state NMR experiments using the full length-M2 WT have shown significant spectral differences that were interpreted to indicate tighter binding for ()- vs ()-rimantadine. However, it was unclear if this correlates with a functional difference in drug binding and inhibition. Using X-ray crystallography, we have determined that both ()- and ()-rimantadine bind to the M2 WT pore with slight differences in the hydration of each enantiomer. However, this does not result in a difference in potency or binding kinetics, as shown by similar values for , , and in electrophysiological assays and for EC values in cellular assays. We concluded that the slight differences in hydration for the ()- and ()-rimantadine enantiomers are not relevant to drug binding or channel inhibition. To further explore the effect of the hydration of the M2 pore on binding affinity, the water structure was evaluated by grand canonical ensemble molecular dynamics simulations as a function of the chemical potential of the water. Initially, the two layers of ordered water molecules between the bound drug and the channel's gating His37 residues mask the drug's chirality. As the chemical potential becomes more unfavorable, the drug translocates down to the lower water layer, and the interaction becomes more sensitive to chirality. These studies suggest the feasibility of displacing the upper water layer and specifically recognizing the lower water layers in novel drugs.

PubMed: 34342217
DOI: 10.1021/acs.biochem.1c00437

実験手法

X-RAY DIFFRACTION (2 Å)