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Spermidine synthase (SpdS; putrescine aminopropyltransferase) catalyzes the transfer of the aminopropyl moiety from decarboxylated<jats:italic>S<\/jats:italic>-adenosylmethionine to putrescine, leading to the formation of spermidine and 5\u2032-methylthioadenosine (MTA). In this work, X-ray crystallography was used to examine ligand complexes of SpdS from the malaria parasite<jats:italic>Plasmodium falciparum<\/jats:italic>(<jats:italic>Pf<\/jats:italic>SpdS). Five crystal structures were determined of<jats:italic>Pf<\/jats:italic>SpdS in complex with MTA and the substrate putrescine, with MTA and spermidine, which was obtained as a result of the enzymatic reaction taking place within the crystals, with dcAdoMet and the inhibitor 4-methylaniline, with MTA and 4-aminomethylaniline, and with a compound predicted in earlier<jats:italic>in silico<\/jats:italic>screening to bind to the active site of the enzyme, benzimidazol-(2-yl)pentan-1-amine (BIPA). In contrast to the other inhibitors tested, the complex with BIPA was obtained without any ligand bound to the dcAdoMet-binding site of the enzyme. The complexes with the aniline compounds and BIPA revealed a new mode of ligand binding to<jats:italic>Pf<\/jats:italic>SpdS. The observed binding mode of the ligands, and the interplay between the two substrate-binding sites and the flexible gatekeeper loop, can be used in the design of new approaches in the search for new inhibitors of SpdS.<\/jats:p>","DOI":"10.1107\/s1399004714027011","type":"journal-article","created":{"date-parts":[[2015,2,26]],"date-time":"2015-02-26T17:43:29Z","timestamp":1424972609000},"page":"484-493","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":13,"title":["Three-dimensional structures of<i>Plasmodium falciparum<\/i>spermidine synthase with bound inhibitors suggest new strategies for drug design"],"prefix":"10.1107","volume":"71","author":[{"given":"Janina","family":"Sprenger","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Svensson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny","family":"H\u00e5lander","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jannette","family":"Carey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lo","family":"Persson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salam","family":"Al-Karadaghi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"329","published-online":{"date-parts":[[2015,2,26]]},"reference":[{"key":"kw5110_bb1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Cryst. 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