Characterization of the differences in the cyclopiazonic acid binding mode to mammalian and P. Falciparum Ca2+ pumps: a computational study.

Handle URI:
http://hdl.handle.net/10754/596775
Title:
Characterization of the differences in the cyclopiazonic acid binding mode to mammalian and P. Falciparum Ca2+ pumps: a computational study.
Authors:
Di Marino, Daniele; D'Annessa, Ilda; Coletta, Andrea; Via, Allegra; Tramontano, Anna
Abstract:
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.
Citation:
Di Marino D, D’Annessa I, Coletta A, Via A, Tramontano A (2015) Characterization of the differences in the cyclopiazonic acid binding mode to mammalian and P. Falciparum Ca 2+ pumps: A computational study . Proteins: Structure, Function, and Bioinformatics 83: 564–574. Available: http://dx.doi.org/10.1002/prot.24734.
Publisher:
Wiley-Blackwell
Journal:
Proteins: Structure, Function, and Bioinformatics
KAUST Grant Number:
KUK-I1-012-43
Issue Date:
1-Mar-2015
DOI:
10.1002/prot.24734
PubMed ID:
25581715
PubMed Central ID:
PMC4342768
Type:
Article
ISSN:
0887-3585
Sponsors:
Grant sponsor: King Abdullah University of Science and Technology (KAUST); Grant number: KUK-I1-012-43; Grant sponsor: PRIN; Grant number: 20108XYHJS; Grant sponsor: IIT Seed Project.
Appears in Collections:
Publications Acknowledging KAUST Support

Full metadata record

DC FieldValue Language
dc.contributor.authorDi Marino, Danieleen
dc.contributor.authorD'Annessa, Ildaen
dc.contributor.authorColetta, Andreaen
dc.contributor.authorVia, Allegraen
dc.contributor.authorTramontano, Annaen
dc.date.accessioned2016-02-21T08:50:25Zen
dc.date.available2016-02-21T08:50:25Zen
dc.date.issued2015-03-01en
dc.identifier.citationDi Marino D, D’Annessa I, Coletta A, Via A, Tramontano A (2015) Characterization of the differences in the cyclopiazonic acid binding mode to mammalian and P. Falciparum Ca 2+ pumps: A computational study . Proteins: Structure, Function, and Bioinformatics 83: 564–574. Available: http://dx.doi.org/10.1002/prot.24734.en
dc.identifier.issn0887-3585en
dc.identifier.pmid25581715en
dc.identifier.doi10.1002/prot.24734en
dc.identifier.urihttp://hdl.handle.net/10754/596775en
dc.description.abstractDespite 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.en
dc.description.sponsorshipGrant sponsor: King Abdullah University of Science and Technology (KAUST); Grant number: KUK-I1-012-43; Grant sponsor: PRIN; Grant number: 20108XYHJS; Grant sponsor: IIT Seed Project.en
dc.publisherWiley-Blackwellen
dc.rightsThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.en
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en
dc.subjectMalariaen
dc.subjectHomology modelingen
dc.subjectMolecular dynamicsen
dc.subjectSercaen
dc.subjectCpaen
dc.subjectPfatp6en
dc.subjectMm-gbsaen
dc.subject.meshPlasmodium falciparumen
dc.titleCharacterization of the differences in the cyclopiazonic acid binding mode to mammalian and P. Falciparum Ca2+ pumps: a computational study.en
dc.typeArticleen
dc.identifier.journalProteins: Structure, Function, and Bioinformaticsen
dc.identifier.pmcidPMC4342768en
dc.contributor.institutionDepartment of Physics, Sapienza University, P.Le Aldo Moro 5, Rome, 00185, Italy.en
kaust.grant.numberKUK-I1-012-43en

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