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Yet, the proteasomes of <jats:italic>Entamoeba histolytica<\/jats:italic> remain understudied. The study\u2019s objective was to analyse the differences in the substrate binding pockets of amoeba proteasomes from those of host, and computational modelling of \u03b25 catalytic subunit, with the goal of finding selective inhibitors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Comparative sequence analysis revealed differences in substrate binding sites of <jats:italic>E. histolytica<\/jats:italic> proteasomes, especially in the S1 and S3 pockets of the catalytic beta subunits, implying differences in substrate preference and susceptibility to inhibitors from host proteasomes. This was strongly supported by significantly lower sensitivity to MG132 mediated inhibition of amoebic proteasome \u03b25 subunit\u2019s chymotryptic activity compared to human proteasomes, also reflected in lower sensitivity of <jats:italic>E. histolytica<\/jats:italic> to MG132 for inhibition of proliferation. Computational models of \u03b24 and \u03b25 subunits, and a docked \u03b24-\u03b25 model revealed a binding pocket between \u03b24-\u03b25, similar to that of <jats:italic>Leishmania tarentolae<\/jats:italic>. Selective inhibitors for visceral leishmaniasis, LXE408 and compound 8, docked well to this pocket. This functional and sequence-based analysis predicts differences between amoebic and host proteasomes that can be utilized to develop rationally designed, selective inhibitors against <jats:italic>E. histolytica.<\/jats:italic><\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13104-024-06848-y","type":"journal-article","created":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T07:03:40Z","timestamp":1722582220000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The 26\u00a0S proteasome in Entamoeba histolytica: divergence of the substrate binding pockets from host proteasomes"],"prefix":"10.1186","volume":"17","author":[{"given":"Nidhi","family":"Joshi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SK Yasir","family":"Hosen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohd.","family":"Fahad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil Raj","family":"Narooka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Gourinath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swati","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,8,2]]},"reference":[{"key":"6848_CR1","doi-asserted-by":"publisher","unstructured":"Pickart CM, Cohen RE. 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