5NCQ

Structure of the (SR) Ca2+-ATPase bound to a Tetrahydrocarbazole and TNP-ATP

5NCQ の概要

• エントリーDOI: 10.2210/pdb5ncq/pdb
• 分子名称: Sarcoplasmic/endoplasmic reticulum calcium ATPase 1, SPIRO(2,4,6-TRINITROBENZENE[1,2A]-2O',3O'-METHYLENE-ADENINE-TRIPHOSPHATE, POTASSIUM ION, ... (6 entities in total)
• 機能のキーワード: p-type atpase, inhibitory complex, calcium-transporting atpase, hydrolase
• 由来する生物種: Oryctolagus cuniculus (Rabbit)
• 細胞内の位置: Endoplasmic reticulum membrane ; Multi-pass membrane protein : P04191
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 112372.45

構造登録者

Bublitz, M.,Kjellerup, L.,O'Hanlon Cohrt, K.,Gordon, S.,Mortensen, A.L.,Clausen, J.D.,Pallin, D.,Hansen, J.B.,Brown, W.D.,Fuglsang, A.,Winther, A.-M.L. (登録日: 2017-03-06, 公開日: 2018-01-10, 最終更新日: 2026-04-15)

主引用文献

Bublitz, M.,Kjellerup, L.,Cohrt, K.O.,Gordon, S.,Mortensen, A.L.,Clausen, J.D.,Pallin, T.D.,Hansen, J.B.,Fuglsang, A.T.,Dalby-Brown, W.,Winther, A.L.
Tetrahydrocarbazoles are a novel class of potent P-type ATPase inhibitors with antifungal activity.
PLoS ONE, 13:e0188620-e0188620, 2018

PubMed Abstract: We have identified a series of tetrahydrocarbazoles as novel P-type ATPase inhibitors. Using a set of rationally designed analogues, we have analyzed their structure-activity relationship using functional assays, crystallographic data and computational modeling. We found that tetrahydrocarbazoles inhibit adenosine triphosphate (ATP) hydrolysis of the fungal H+-ATPase, depolarize the fungal plasma membrane and exhibit broad-spectrum antifungal activity. Comparative inhibition studies indicate that many tetrahydrocarbazoles also inhibit the mammalian Ca2+-ATPase (SERCA) and Na+,K+-ATPase with an even higher potency than Pma1. We have located the binding site for this compound class by crystallographic structure determination of a SERCA-tetrahydrocarbazole complex to 3.0 Å resolution, finding that the compound binds to a region above the ion inlet channel of the ATPase. A homology model of the Candida albicans H+-ATPase based on this crystal structure, indicates that the compounds could bind to the same pocket and identifies pocket extensions that could be exploited for selectivity enhancement. The results of this study will aid further optimization towards selective H+-ATPase inhibitors as a new class of antifungal agents.

PubMed: 29293507
DOI: 10.1371/journal.pone.0188620

実験手法

X-RAY DIFFRACTION (3 Å)