Abstract:
:The causative agent of African sleeping sickness, Trypanosoma brucei , undergoes an unusual mitochondrial RNA editing process that is essential for its survival. RNA editing terminal uridylyl transferase 2 of T. brucei (TbRET2) is an indispensable component of the editosome machinery that performs this editing. TbRET2 is required to maintain the vitality of both the insect and bloodstream forms of the parasite, and with its high-resolution crystal structure, it poses as a promising pharmaceutical target. Neither the exclusive requirement of uridine 5'-triphosphate (UTP) for catalysis, nor the RNA primer preference of TbRET2 is well-understood. Using all-atom explicitly solvated molecular dynamics (MD) simulations, we investigated the effect of UTP binding on TbRET2 structure and dynamics, as well as the determinants governing TbRET2's exclusive UTP preference. Through our investigations of various nucleoside triphosphate substrates (NTPs), we show that UTP preorganizes the binding site through an extensive water-mediated H-bonding network, bringing Glu424 and Arg144 side chains to an optimum position for RNA primer binding. In contrast, cytosine 5'-triphosphate (CTP) and adenosine 5'-triphosphate (ATP) cannot achieve this preorganization and thus preclude productive RNA primer binding. Additionally, we have located ligand-binding "hot spots" of TbRET2 based on the MD conformational ensembles and computational fragment mapping. TbRET2 reveals different binding pockets in the apo and UTP-bound MD simulations, which could be targeted for inhibitor design.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Demir Ö,Amaro REdoi
10.1021/ci3001327subject
Has Abstractpub_date
2012-05-25 00:00:00pages
1308-18issue
5eissn
1549-9596issn
1549-960Xjournal_volume
52pub_type
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