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Title: From bacterial to human dihydrouridine synthase: automated structure determination

The crystal structure of a human dihydrouridine synthase, an enzyme associated with lung cancer, with 18% sequence identity to a T. maritima enzyme, has been determined at 1.9 Å resolution by molecular replacement after extensive molecular remodelling of the template. 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 Å 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 β-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 fightmore » against lung cancer.« less
Authors:
;  [1] ;  [2] ;  [3] ; ;  [1]
  1. The University of York, Heslington, York YO10 5DD (United Kingdom)
  2. University of Oxford, Headington, Oxford OX3 7BN (United Kingdom)
  3. Ludwig-Maximilians-University Munich, Feodor-Lynen-Strasse 25, 81377 Munich (Germany)
Publication Date:
OSTI Identifier:
22389073
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 71; Journal Issue: Pt 7; Other Information: PMCID: PMC4498606; PMID: 26143927; PUBLISHER-ID: rr5097; OAI: oai:pubmedcentral.nih.gov:4498606; Copyright (c) Whelan et al. 2015; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; CARCINOGENESIS; CRYSTAL STRUCTURE; ENZYMES; INTERACTIONS; LUNGS; NEOPLASMS; REDUCTION; RESIDUES; RESOLUTION; URIDINE; VIABILITY