Identification of a 1-deoxy-D-xylulose-5-phosphate synthase (DXS) mutant with improved crystallographic properties.
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Authors
Gierse, Robin MReddem, Eswar R
Alhayek, Alaa
Baitinger, Dominik
Hamid, Zhoor
Jakobi, Harald
Laber, Bernd
Lange, Gudrun
Hirsch, Anna K H
Groves, Matthew R
Issue Date
2021-01-05
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Show full item recordAbstract
In this report, we describe a truncated Deinococcus radiodurans 1-deoxy-D-xylulose-5-phosphate synthase (DXS) protein that retains enzymatic activity, while slowing protein degradation and showing improved crystallization properties. With modern drug-design approaches relying heavily on the elucidation of atomic interactions of potential new drugs with their targets, the need for co-crystal structures with the compounds of interest is high. DXS itself is a promising drug target, as it catalyzes the first reaction in the 2-C-methyl-D-erythritol 4-phosphate (MEP)-pathway for the biosynthesis of the universal precursors of terpenes, which are essential secondary metabolites. In contrast to many bacteria and pathogens, which employ the MEP pathway, mammals use the distinct mevalonate-pathway for the biosynthesis of these precursors, which makes all enzymes of the MEP-pathway potential new targets for the development of anti-infectives. However, crystallization of DXS has proven to be challenging: while the first X-ray structures from Escherichia coli and D. radiodurans were solved in 2004, since then only two additions have been made in 2019 that were obtained under anoxic conditions. The presented site of truncation can potentially also be transferred to other homologues, opening up the possibility for the determination of crystal structures from pathogenic species, which until now could not be crystallized. This manuscript also provides a further example that truncation of a variable region of a protein can lead to improved structural data.Citation
Biochem Biophys Res Commun. 2021 Jan 5;539:42-47. doi: 10.1016/j.bbrc.2020.12.069. Epub ahead of print.Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.Publisher
ElsevierPubMed ID
33421767Type
ArticleLanguage
enEISSN
1090-2104ae974a485f413a2113503eed53cd6c53
10.1016/j.bbrc.2020.12.069
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- Creative Commons
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