Structural highlights
Function
DUS2L_HUMAN Dihydrouridine synthase. Catalyzes the synthesis of dihydrouridine, a modified base found in the D-loop of most tRNAs. Negatively regulates the activation of EIF2AK2/PKR.[1] [2]
Publication Abstract from PubMed
The reduction of uridine to dihydrouridine at specific positions in tRNA is catalysed by dihydrouridine synthase (Dus) enzymes. Increased expression of human dihydrouridine synthase 2 (hDus2) has been linked to pulmonary carcinogenesis, while its knockdown decreased cancer cell line viability, suggesting that it may serve as a valuable target for therapeutic intervention. Here, the X-ray crystal structure of a construct of hDus2 encompassing the catalytic and tRNA-recognition domains (residues 1-340) determined at 1.9 A resolution is presented. It is shown that the structure can be determined automatically by phenix.mr_rosetta starting from a bacterial Dus enzyme with only 18% sequence identity and a significantly divergent structure. The overall fold of the human Dus2 is similar to that of bacterial enzymes, but has a larger recognition domain and a unique three-stranded antiparallel beta-sheet insertion into the catalytic domain that packs next to the recognition domain, contributing to domain-domain interactions. The structure may inform the development of novel therapeutic approaches in the fight against lung cancer.
From bacterial to human dihydrouridine synthase: automated structure determination.,Whelan F, Jenkins HT, Griffiths SC, Byrne RT, Dodson EJ, Antson AA Acta Crystallogr D Biol Crystallogr. 2015 Jul 1;71(Pt 7):1564-71. doi:, 10.1107/S1399004715009220. Epub 2015 Jun 30. PMID:26143927[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kato T, Daigo Y, Hayama S, Ishikawa N, Yamabuki T, Ito T, Miyamoto M, Kondo S, Nakamura Y. A novel human tRNA-dihydrouridine synthase involved in pulmonary carcinogenesis. Cancer Res. 2005 Jul 1;65(13):5638-46. PMID:15994936 doi:http://dx.doi.org/65/13/5638
- ↑ Mittelstadt M, Frump A, Khuu T, Fowlkes V, Handy I, Patel CV, Patel RC. Interaction of human tRNA-dihydrouridine synthase-2 with interferon-induced protein kinase PKR. Nucleic Acids Res. 2008 Feb;36(3):998-1008. Epub 2007 Dec 20. PMID:18096616 doi:http://dx.doi.org/10.1093/nar/gkm1129
- ↑ Whelan F, Jenkins HT, Griffiths SC, Byrne RT, Dodson EJ, Antson AA. From bacterial to human dihydrouridine synthase: automated structure determination. Acta Crystallogr D Biol Crystallogr. 2015 Jul 1;71(Pt 7):1564-71. doi:, 10.1107/S1399004715009220. Epub 2015 Jun 30. PMID:26143927 doi:http://dx.doi.org/10.1107/S1399004715009220
