PMID- 31552962
OWN - NLM
STAT- MEDLINE
DCOM- 20191202
LR  - 20191202
IS  - 1463-9084 (Electronic)
IS  - 1463-9076 (Linking)
VI  - 21
IP  - 39
DP  - 2019 Oct 9
TI  - Allosteric modulation of the sarcoplasmic reticulum Ca(2+) ATPase by thapsigargin 
      via decoupling of functional motions.
PG  - 21991-21995
LID - 10.1039/c9cp04736k [doi]
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.
FAU - Saleh, Noureldin
AU  - Saleh N
AD  - Linderstrom-Lang Centre for Protein Science, Dept. of Biology, University of 
      Copenhagen, Copenhagen, Denmark. lindorff@bio.ku.dk.
FAU - Wang, Yong
AU  - Wang Y
FAU - Nissen, Poul
AU  - Nissen P
FAU - Lindorff-Larsen, Kresten
AU  - Lindorff-Larsen K
LA  - eng
PT  - Journal Article
PL  - England
TA  - Phys Chem Chem Phys
JT  - Physical chemistry chemical physics : PCCP
JID - 100888160
RN  - 0 (Cations, Divalent)
RN  - 0 (Enzyme Inhibitors)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Allosteric Site
MH  - Biological Transport
MH  - Calcium/chemistry
MH  - Cations, Divalent/chemistry
MH  - Enzyme Inhibitors/*chemistry
MH  - Molecular Dynamics Simulation
MH  - Protein Binding
MH  - Protein Conformation
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/*antagonists & inhibitors
MH  - Signal Transduction
MH  - Thapsigargin/*chemistry
EDAT- 2019/09/26 06:00
MHDA- 2019/12/04 06:00
CRDT- 2019/09/26 06:00
PHST- 2019/09/26 06:00 [pubmed]
PHST- 2019/12/04 06:00 [medline]
PHST- 2019/09/26 06:00 [entrez]
AID - 10.1039/c9cp04736k [doi]
PST - ppublish
SO  - Phys Chem Chem Phys. 2019 Oct 9;21(39):21991-21995. doi: 10.1039/c9cp04736k.