Allosteric modulation of the sarcoplasmic reticulum Ca2+ ATPase by thapsigargin via decoupling of functional motions. Issue 39 (25th September 2019)

• Record Type: Journal Article
• Authors: Saleh, Noureldin; Wang, Yong; Nissen, Poul; Lindorff-Larsen, Kresten
• Is Part Of: Physical chemistry chemical physics. Volume 21:Issue 39(2019)
• Page Start: 21991
• Page End: 21995
• Publication Date: 2019-09-25
• Subjects: Chemistry, Physical and theoretical -- Periodicals; 541.3
• DOI: 10.1039/c9cp04736k
• Languages: English
• ISSNs: 1463-9076

Abstract

Abstract : Thapsigargin binding to the Ca 2+ -ATPase SERCA induces a conformational change in the transmembrane regions without regulation of the cytoplasmic domains, and causes a conformational change in the cytoplasmic domains uncoupled from nucleotide binding. Abstract : The sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) is a widely studied member of the large family of phosphorylation(P)-type ATPase membrane transporters. Ligands and nucleotide binding naturally modulate the conformational space of P-type ATPases through allosteric inter-domain communications. Whereas many inhibitory ATPase ligands act by directly blocking substrate uptake or release, SERCA is a target for thapsigargin (TG), a plant-derived natural product that allosterically inhibits the transport cycle. While thapsigargin's inhibitory effects on SERCA have been widely studied experimentally, the molecular mechanisms underlying these remain incompletely understood. Here, we apply modelling and molecular simulations to probe the effects of TG binding to the major functional states along SERCA's reaction cycle. Our results provide insight into the atomic-level details of the conformational changes induced by TG binding to SERCA, and suggest mechanisms for its effect. Since other P-type ATPases share closely related reaction cycles, our data suggests that similar modulators might exist for these.