{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T14:55:46Z","timestamp":1785596146381,"version":"3.56.0"},"reference-count":38,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005156","name":"Alexander von Humboldt-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    expresses four heat shock protein 90 (Hsp90) members. Among these, one, glucose\u2010regulated protein 94 (\n                    <jats:italic>Pf<\/jats:italic>\n                    Grp94), is localized in the endoplasmic reticulum (ER). Both the cytosolic and ER\u2010based Hsp90s are essential for parasite survival under all growth conditions. The cytosolic version has been extensively studied and has been targeted in several efforts through the repurposing of anticancer therapeutics as antimalarial drugs. However,\n                    <jats:italic>Pf<\/jats:italic>\n                    Grp94 has not been fully characterized and some of its functions related to the ER stress response are not fully understood. Structural analysis of the recombinant full\u2010length\n                    <jats:italic>Pf<\/jats:italic>\n                    Grp94 protein showed a predominantly \u03b1\u2010helical secondary structure and its thermal resilience was modulated by 5\u2032\u2010\n                    <jats:italic>N<\/jats:italic>\n                    \u2010ethyl\u2010carboxamide\u2010adenosine (NECA) and nucleotides ATP\/ADP.\n                    <jats:italic>Pf<\/jats:italic>\n                    Grp94 exhibits ATPase activity and suppressed heat\u2010induced aggregation of a model substrate, malate dehydrogenase, in a nucleotide\u2010dependent manner. However, these\n                    <jats:italic>Pf<\/jats:italic>\n                    Grp94 chaperone functions were abrogated by NECA. Molecular docking and molecular dynamics (MD) simulations showed that NECA interacted with unique residues on\n                    <jats:italic>Pf<\/jats:italic>\n                    Grp94, which could be potentially exploited for selective drug design. Finally, using parasites maintained at the red blood stage, NECA exhibited moderate antiplasmodial activity (IC\n                    <jats:sub>50<\/jats:sub>\n                    of 4.3, 7.4, and 10.0\u2009\u03bcM) against three different\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    strains. Findings from this study provide the first direct evidence for the correlation between in silico, biochemical, and in\u00a0vitro data toward utilizing the ER\u2010based chaperone,\n                    <jats:italic>Pf<\/jats:italic>\n                    Grp94, as a drug target against the malaria parasites.\n                  <\/jats:p>","DOI":"10.1002\/prot.26779","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T07:30:15Z","timestamp":1734075015000},"page":"957-971","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Characterization and Inhibition of the Chaperone Function of\n                    <i>Plasmodium falciparum<\/i>\n                    Glucose\u2010Regulated Protein 94\u2009\n                    <scp>kDa<\/scp>\n                    (\n                    <i>Pf<\/i>\n                    <scp>Grp94<\/scp>\n                    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Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erick","family":"Strauss","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Stellenbosch University  Stellenbosch South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8689-0152","authenticated-orcid":false,"given":"Tawanda","family":"Zininga","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Stellenbosch University  Stellenbosch South 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