{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:45:36Z","timestamp":1762101936909},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,10,27]],"date-time":"2016-10-27T00:00:00Z","timestamp":1477526400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,10,27]],"date-time":"2016-10-27T00:00:00Z","timestamp":1477526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Human African Trypanosomiasis (HAT) is a life-threatening infectious disease caused by the protozoan parasite, <jats:italic>Trypanosoma brucei<\/jats:italic> (<jats:italic>Tbr<\/jats:italic>). Due to the debilitating side effects of the current therapeutics and the emergence of resistance to these drugs, new medications for this disease need to be developed. One potential new drug target is 6-oxopurine phosphoribosyltransferase (PRT), an enzyme central to the purine salvage pathway and whose activity is critical for the production of the nucleotides (GMP and IMP) required for DNA\/RNA synthesis within this protozoan parasite. Here, the first crystal structures of this enzyme have been determined, these in complex with GMP and IMP and with three acyclic nucleoside phosphonate (ANP) inhibitors. The K<jats:sub>i<\/jats:sub> values for GMP and IMP are 30.5\u2009\u03bcM and 77\u2009\u03bcM, respectively. Two of the ANPs have K<jats:sub>i<\/jats:sub> values considerably lower than for the nucleotides, 2.3\u2009\u03bcM (with guanine as base) and 15.8\u2009\u03bcM (with hypoxanthine as base). The crystal structures show that when two of the ANPs bind, they induce an unusual conformation change to the loop where the reaction product, pyrophosphate, is expected to bind. This and other structural differences between the <jats:italic>Tbr<\/jats:italic> and human enzymes suggest selective inhibitors for the <jats:italic>Tbr<\/jats:italic> enzyme can be designed.<\/jats:p>","DOI":"10.1038\/srep35894","type":"journal-article","created":{"date-parts":[[2016,10,27]],"date-time":"2016-10-27T09:12:35Z","timestamp":1477559555000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Crystal structures and inhibition of Trypanosoma brucei hypoxanthine\u2013guanine phosphoribosyltransferase"],"prefix":"10.1038","volume":"6","author":[{"given":"David","family":"Ter\u00e1n","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Hockov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"\u010cesnek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alena","family":"Z\u00edkov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lieve","family":"Naesens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dianne T.","family":"Keough","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke W.","family":"Guddat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,10,27]]},"reference":[{"key":"BFsrep35894_CR1","unstructured":"W.H.O. Control and surveillance of human African trypanosomiasis. World Health Organ Tech Rep Ser, 1\u2013237 (2013)."},{"key":"BFsrep35894_CR2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.actatropica.2015.06.003","volume":"150","author":"J Keating","year":"2015","unstructured":"Keating, J., Yukich, J. O., Sutherland, C. S., Woods, G. & Tediosi, F. Human African trypanosomiasis prevention, treatment and control costs: A systematic review. Acta Trop 150, 4\u201313 (2015).","journal-title":"Acta Trop"},{"key":"BFsrep35894_CR3","first-page":"257","volume":"6","author":"JR Franco","year":"2014","unstructured":"Franco, J. R., Simarro, P. P., Diarra, A. & Jannin, J. G. Epidemiology of human African trypanosomiasis. Clin Epidemiol 6, 257\u2013275 (2014).","journal-title":"Clin Epidemiol"},{"key":"BFsrep35894_CR4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2015.00032","volume":"6","author":"JC Munday","year":"2015","unstructured":"Munday, J. C., Settimo, L. & de Koning, H. P. Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei. Front Pharmacol 6, 1\u201310 (2015).","journal-title":"Front Pharmacol"},{"key":"BFsrep35894_CR5","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ijpddr.2013.12.001","volume":"4","author":"A Luscher","year":"2014","unstructured":"Luscher, A., Lamprea-Burgunder, E., Graf, F. E., de Koning, H. P. & Maser, P. Trypanosoma brucei adenine-phosphoribosyltransferases mediate adenine salvage and aminopurinol susceptibility but not adenine toxicity. Int J Parasitol Drugs Drug Resist 4, 55\u201363 (2014).","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"BFsrep35894_CR6","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ijpddr.2015.04.002","volume":"5","author":"FE Graf","year":"2015","unstructured":"Graf, F. E. et al. Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol-pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates. Int J Parasitol Drugs Drug Resist 5, 65\u201368 (2015).","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"BFsrep35894_CR7","doi-asserted-by":"crossref","first-page":"e91372","DOI":"10.1371\/journal.pone.0091372","volume":"9","author":"S Mogk","year":"2014","unstructured":"Mogk, S. et al. Cyclical appearance of African trypanosomes in the cerebrospinal fluid: new insights in how trypanosomes enter the CNS. PLoS One 9, e91372 (2014).","journal-title":"PLoS One"},{"key":"BFsrep35894_CR8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2164-11-222","volume":"11","author":"MA Doyle","year":"2010","unstructured":"Doyle, M. A., Gasser, R. B., Woodcroft, B. J., Hall, R. S. & Ralph, S. A. Drug target prediction and prioritization: using orthology to predict essentiality in parasite genomes. 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