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Genes 2017, 8(6), 166; doi:10.3390/genes8060166

A Comparative Study of the Structural Dynamics of Four Terminal Uridylyl Transferases

1,†,‡
,
1,‡
and
1,2,*
1
Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
2
National Biomedical Computation Resource, University of California, San Diego, La Jolla, CA 92093, USA
Current Address: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
These authors contributed equally to this study.
*
Author to whom correspondence should be addressed.
Academic Editor: H. Ulrich Göringer
Received: 22 March 2017 / Revised: 22 May 2017 / Accepted: 7 June 2017 / Published: 20 June 2017
(This article belongs to the Special Issue RNA Editing)
View Full-Text   |   Download PDF [2570 KB, uploaded 20 June 2017]   |  

Abstract

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’ 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’s and TbTUT4’s 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’s larger side pocket can be exploited to achieve selective inhibitor design as FTMap identifies it as a druggable pocket. View Full-Text
Keywords: TUTases; terminal uridylyl transferases; POVME; electrostatics; pocket volume; pocket shape; RET1; RET2; MEAT1; TUT4; Trypanosoma brucei TUTases; terminal uridylyl transferases; POVME; electrostatics; pocket volume; pocket shape; RET1; RET2; MEAT1; TUT4; Trypanosoma brucei
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Cheng, K.J.; Demir, Ö.; Amaro, R.E. A Comparative Study of the Structural Dynamics of Four Terminal Uridylyl Transferases. Genes 2017, 8, 166.

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