Water-Mediated Interactions Influence the Binding of Thapsigargin to Sarco/Endoplasmic Reticulum Calcium Adenosinetriphosphatase

Abstract

A crystal structure suggests four water molecules are present in the binding cavity of thapsigargin in sarco/endoplasmic reticulum calcium ATPase (SERCA). Computational chemistry indicates that three of these water molecules mediate an extensive hydrogen-bonding network between thapsigargin and the backbone of SERCA. The orientation of the thapsigargin molecule in SERCA is crucially dependent on these interactions. The hypothesis has been verified by measuring the affinity of newly synthesized model compounds, which are prevented from participating in such water-mediated interactions as hydrogen-bond donors.

G protein coupled receptor interactions with cholesterol deep in the membrane

“…A useful contrast can be drawn with the hydrophobic inhibitor thapsigargin that binds with high affinity to a specific site on the lipid-exposed surface of the calcium ATPase of sarcoplasmic reticulum, the specificity being attributed to an extensive hydrogen-bonding network between the protein and the eight oxygen atoms on thapsigargin [15], an option not open to cholesterol with its single -OH group. 5 The fact that cholesterol contains only a single polar group makes it more hydrophobic than a phospholipid; the calculated free energy of partition for a cholesterol monomer between water and hydrocarbon is comparable to that of an alcohol of C20 chain length [16].…”

Computer modelling reveals new conformers of the ATP binding loop of Na+/K+-ATPase involved in the transphosphorylation process of the sodium pump

“…The tertiary structure of Na + /K + -ATPase has been solved at high resolution by X-ray crystallography (Kanai et al, 2013; Laursen et al, 2015; Laursen et al, 2013; Morth et al, 2011; Morth et al, 2007; Nyblom et al, 2013; Ogawa et al, 2015; Ogawa et al, 2009; Shinoda et al, 2009; Yatime et al, 2011) and also partially several N-domain structures by X-ray crystallography (Håkansson, 2003) and NMR (Mark Hilge et al, 2003). In addition, several crystallographic structures of Ca 2+ -ATPase were reported (Akin et al, 2013; Bublitz et al, 2015; Clausen et al, 2013; Drachmann et al, 2014; Jensen et al, 2006; Laursen et al, 2009; MacLennan & Green, 2000; Moncoq, Trieber & Young, 2007; Obara et al, 2005; Olesen et al, 2007; Olesen et al, 2004; Paulsen et al, 2013; Sacchetto et al, 2012; Sohoel et al, 2006; Sonntag et al, 2011; Sorensen, Moller & Nissen, 2004; Takahashi, Kondou & Toyoshima, 2007; Toyoshima, 2008; Toyoshima et al, 2013; Toyoshima & Mizutani, 2004; Toyoshima et al, 2000; Toyoshima & Nomura, 2002; Winther et al, 2010; Winther et al, 2013). …”

Comparing crystal structures of Ca2+‐ATPase in the presence of different lipids

“…Otherwise, the direct structural implications of the lipid composition on SERCA have not been described in any systematic way. Crystal structures of SERCA with bound lipids have been published [4,[9][10][11][12][13][14][15], but no comparative description of the ensuing lipid-protein interactions has been carried out so far.…”