Allosteric modulation of the sarcoplasmic reticulum Ca²⁺ ATPase by thapsigargin via decoupling of functional motions

TY - JOUR

T1 - Allosteric modulation of the sarcoplasmic reticulum Ca2+ ATPase by thapsigargin via decoupling of functional motions

AU - Saleh, Noureldin

AU - Wang, Yong

AU - Nissen, Poul

AU - Lindorff-Larsen, Kresten

PY - 2019

Y1 - 2019

N2 - The sarcoplasmic reticulum Ca2+-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.

AB - The sarcoplasmic reticulum Ca2+-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.

U2 - 10.1039/c9cp04736k

DO - 10.1039/c9cp04736k

M3 - Journal article

C2 - 31552962

SN - 1463-9076

VL - 21

SP - 21991

EP - 21995

JO - Physical Chemistry Chemical Physics

JF - Physical Chemistry Chemical Physics

IS - 39

ER -