{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:24:34Z","timestamp":1791829474148,"version":"4.3.4"},"reference-count":23,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2017,6,20]],"date-time":"2017-06-20T00:00:00Z","timestamp":1497916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DP2OD007237"],"award-info":[{"award-number":["DP2OD007237"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["NIGMS P41-GM103426"],"award-info":[{"award-number":["NIGMS P41-GM103426"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000930","name":"NSF","doi-asserted-by":"publisher","award":["CHE060073N"],"award-info":[{"award-number":["CHE060073N"]}],"id":[{"id":"10.13039\/501100000930","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>African trypanosomiasis occurs in 36 countries in sub-Saharan Africa with 10,000 reported cases annually. No definitive remedy is currently available and if left untreated, the disease becomes fatal. Structural and biochemical studies of trypanosomal terminal uridylyl transferases (TUTases) demonstrated their functional role in extensive uridylate insertion\/deletion of RNA. Trypanosoma brucei RNA Editing TUTase 1 (TbRET1) is involved in guide RNA 3\u2019 end uridylation and maturation, while TbRET2 is responsible for U-insertion at RNA editing sites. Two additional TUTases called TbMEAT1 and TbTUT4 have also been reported to share similar function. TbRET1 and TbRET2 are essential enzymes for the parasite viability making them potential drug targets. For this study, we clustered molecular dynamics (MD) trajectories of four TUTases based on active site shape measured by Pocket Volume Measurer (POVME) program. Among the four TUTases, TbRET1 exhibited the largest average pocket volume, while TbMEAT1\u2019s and TbTUT4\u2019s active sites displayed the most flexibility. A side pocket was also identified within the active site in all TUTases with TbRET1 having the most pronounced. Our results indicate that TbRET1\u2019s larger side pocket can be exploited to achieve selective inhibitor design as FTMap identifies it as a druggable pocket.<\/jats:p>","DOI":"10.3390\/genes8060166","type":"journal-article","created":{"date-parts":[[2017,6,20]],"date-time":"2017-06-20T10:15:38Z","timestamp":1497953738000},"page":"166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Comparative Study of the Structural Dynamics of Four Terminal Uridylyl Transferases"],"prefix":"10.3390","volume":"8","author":[{"given":"Kevin","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Chemistry &amp; Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zlem","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Chemistry &amp; Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rommie","family":"Amaro","sequence":"additional","affiliation":[{"name":"Department of Chemistry &amp; Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA"},{"name":"National Biomedical Computation Resource, University of California, San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1126\/science.1112642","article-title":"The genome of the african trypanosome trypanosoma brucei","volume":"309","author":"Berriman","year":"2005","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1021\/ci3001327","article-title":"Elements of nucleotide specificity in the trypanosoma brucei mitochondrial RNA editing enzyme RET2","volume":"52","author":"Demir","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.actatropica.2013.07.022","article-title":"Evaluating the developmental toxicity of trypanocidal nitroaromatic compounds on zebrafish","volume":"128","author":"Djumpah","year":"2013","journal-title":"Acta Trop."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.drudis.2016.11.001","article-title":"Molecular dynamics-driven drug discovery: Leaping forward with confidence","volume":"22","author":"Ganesan","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1038\/sj.emboj.7600861","article-title":"Structural basis for UTP specificity of RNA editing tutases from trypanosoma brucei","volume":"24","author":"Deng","year":"2005","journal-title":"EMBO J"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1002\/wrna.82","article-title":"Uridine insertion\/deletion editing in trypanosomes: A playground for RNA-guided information transfer","volume":"2","author":"Aphasizhev","year":"2011","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.biochi.2014.01.003","article-title":"Mitochondrial RNA editing in trypanosomes: Small rnas in control","volume":"100","author":"Aphasizhev","year":"2014","journal-title":"Biochimie"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.jmb.2006.11.065","article-title":"UTP-bound and apo structures of a minimal RNA uridylyltransferase","volume":"366","author":"Stagno","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3751","DOI":"10.1093\/nar\/25.19.3751","article-title":"The mechanism of u insertion\/deletion RNA editing in kinetoplastid mitochondria","volume":"25","author":"Alfonzo","year":"1997","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7701","DOI":"10.1093\/nar\/gkp854","article-title":"Comprehensive classification of nucleotidyltransferase fold proteins: Identification of novel families and their representatives in human","volume":"37","author":"Kuchta","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1128\/MCB.01281-09","article-title":"Ret1-catalyzed uridylylation shapes the mitochondrial transcriptome in trypanosoma brucei","volume":"30","author":"Aphasizheva","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10862","DOI":"10.1093\/nar\/gkw917","article-title":"RNA editing tutase 1: Structural foundation of substrate recognition, complex interactions and drug targeting","volume":"44","author":"Rajappa","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.jmb.2010.04.021","article-title":"Structure of the mitochondrial editosome-like complex associated tutase 1 reveals divergent mechanisms of UTP selection and domain organization","volume":"399","author":"Stagno","year":"2010","journal-title":"J. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1146\/annurev-biophys-042910-155245","article-title":"Biomolecular simulation: A computational microscope for molecular biology","volume":"41","author":"Dror","year":"2012","journal-title":"Annu. Rev. Biophys."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.sbi.2009.03.004","article-title":"Long-timescale molecular dynamics simulations of protein structure and function","volume":"19","author":"Klepeis","year":"2009","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1021\/cr040426m","article-title":"Molecular dynamics: Survey of methods for simulating the activity of proteins","volume":"106","author":"Adcock","year":"2006","journal-title":"Chem. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/cbdd.12302","article-title":"Computer-aided discovery of trypanosoma brucei RNA-editing terminal uridylyl transferase 2 inhibitors","volume":"84","author":"Demir","year":"2014","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"Vmd: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"256","DOI":"10.4208\/cicp.170711.111111s","article-title":"Delensembleelec: Computing ensemble-averaged electrostatics using delphi","volume":"13","author":"Votapka","year":"2013","journal-title":"Commun. Comput. Phys."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5047","DOI":"10.1021\/ct500381c","article-title":"Povme 2.0: An enhanced tool for determining pocket shape and volume characteristics","volume":"10","author":"Durrant","year":"2014","journal-title":"J. Chem. Theory Comput."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wagner, J.R., Sorensen, J., Hensley, N., Wong, C., Zhu, C., and Amaro, R.E. (2017). Povme 3.0: Software for mapping binding pocket flexibility, Submitted.","DOI":"10.1021\/acs.jctc.7b00500"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Roberts, E., Eargle, J., Wright, D., and Luthey-Schulten, Z. (2006). Multiseq: Unifying sequence and structure data for evolutionary analysis. BMC Bioinform., 7.","DOI":"10.1186\/1471-2105-7-382"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/nprot.2015.043","article-title":"The ftmap family of web servers for determining and characterizing ligand-binding hot spots of proteins","volume":"10","author":"Kozakov","year":"2015","journal-title":"Nat. Protoc."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/8\/6\/166\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:39:42Z","timestamp":1760207982000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/8\/6\/166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,20]]},"references-count":23,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2017,6]]}},"alternative-id":["genes8060166"],"URL":"https:\/\/doi.org\/10.3390\/genes8060166","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,20]]}}}