Projekt per år
Sammanfattning
Dermatan sulfate epimerase 1 (DS-epi1, EC 5.1.3.19) catalyzes the conversion of d-glucuronic acid to l-iduronic acid on the polymer level, a key step in the biosynthesis of the glycosaminoglycan dermatan sulfate. Here, we present the first crystal structure of the catalytic domains of DS-epi1, solved at 2.4 Å resolution, as well as a model of the full-length luminal protein obtained by a combination of macromolecular crystallography and targeted cross-linking mass spectrometry. Based on docking studies and molecular dynamics simulations of the protein structure and a chondroitin substrate, we suggest a novel mechanism of DS-epi1, involving a His/double-Tyr motif. Our work uncovers detailed information about the domain architecture, active site, metal-coordinating center and pattern of N-glycosylation of the protein. Additionally, the structure of DS-epi1 reveals a high structural similarity to proteins from several families of bacterial polysaccharide lyases. DS-epi1 is of great importance in a range of diseases, and the structure provides a necessary starting point for design of active site inhibitors.
Originalspråk | engelska |
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Sidor (från-till) | 1869-1885 |
Antal sidor | 17 |
Tidskrift | Chemical Science |
Volym | 12 |
Nummer | 5 |
DOI | |
Status | Published - 2021 feb. 7 |
Ämnesklassifikation (UKÄ)
- Cell- och molekylärbiologi
- Biokemi och molekylärbiologi
Fingeravtryck
Utforska forskningsämnen för ”The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms”. Tillsammans bildar de ett unikt fingeravtryck.Projekt
- 1 Aktiva
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DSepi1: Small molecules that interfere with the biosynthesis of dermatan sulfate for exploration of cell surface carbohydrates and use as cancer therapy
Ellervik, U. (Forskare), Tykesson, E. (Forskare), Malmström, A. (Forskare) & Mastio, R. (Forskarstuderande)
2014/01/01 → …
Projekt: Forskning