Di Marino, Daniele; D'Annessa, Ilda; Coletta, Andrea; Via, Allegra; Tramontano, Anna(Proteins: Structure, Function, and Bioinformatics, Wiley, 2015-02-10)[Article]
Despite the investments in malaria research, an effective vaccine has not yet been developed and the causative parasites are becoming increasingly resistant to most of the available drugs. PfATP6, the sarco/endoplasmic reticulum Ca2+ pump (SERCA) of P. falciparum, has been recently genetically validated as a potential antimalarial target and cyclopiazonic acid (CPA) has been found to be a potent inhibitor of SERCAs in several organisms, including P. falciparum. In position 263, PfATP6 displays a leucine residue, whilst the corresponding position in the mammalian SERCA is occupied by a glutamic acid. The PfATP6 L263E mutation has been studied in relation to the artemisinin inhibitory effect on P. falciparum and recent studies have provided evidence that the parasite with this mutation is more susceptible to CPA. Here, we characterized, for the first time, the interaction of CPA with PfATP6 and its mammalian counterpart to understand similarities and differences in the mode of binding of the inhibitor to the two Ca2+ pumps. We found that, even though CPA does not directly interact with the residue in position 263, the presence of a hydrophobic residue in this position in PfATP6 rather than a negatively charged one, as in the mammalian SERCA, entails a conformational arrangement of the binding pocket which, in turn, determines a relaxation of CPA leading to a different binding mode of the compound. Our findings highlight differences between the plasmodial and human SERCA CPA-binding pockets that may be exploited to design CPA derivatives more selective toward PfATP6.
Export search results
The export option will allow you to export the current search results of the entered query to a file. Different
formats are available for download. To export the items, click on the button corresponding with the preferred download format.
By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.
For anonymous users the allowed maximum amount is 50 search results.
To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export.
The amount of items that can be exported at once is similarly restricted as the full export.
After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.