Structures, Properties, and Dynamics of Intermediates in eEF2-Diphthamide Biosynthesis

Billod, Jean-MarcGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Göteborgs universitet; Center for Biological Research, ESP (författare)

The eukaryotic translation Elongation Factor 2 (eEF2) is an essential enzyme in protein synthesis. eEF2 contains a unique modification of a histidine (His699 in yeast; HIS) into diphthamide (DTA), obtained via 3-amino-3-carboxypropyl (ACP) and diphthine (DTI) intermediates in the biosynthetic pathway. This essential and unique modification is also vulnerable, in that it can be efficiently targeted by NAD(+)-dependent ADP-ribosylase toxins, such as diphtheria toxin (DT). However, none of the intermediates in the biosynthesis path is equally vulnerable against the toxins. This study aims to address the different susceptibility of DTA and its precursors against bacterial toxins. We have herein undertaken a detailed in silico study of the structural features and dynamic motion of different His699 intermediates along the diphthamide synthesis pathway (HIS, ACP, DTI, DTA). The study points out that DTA forms a strong hydrogen bond with an asparagine which might explain the ADP-ribosylation mechanism caused by the diphtheria toxin (DT). Finally, in silico mutagenesis studies were performed on the DTA modified protein, in order to hamper the formation of such a hydrogen bond. The results indicate that the mutant structure might in fact be less susceptible to attack by DT and thereby behave similarly to DTI in this respect.

Saenz Mendez, PatriciaGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Göteborgs Universitet; Universidad de la República, URY(Swepub:kau)patrmend (författare)
Blomberg, Anders,1956Gothenburg University,Göteborgs universitet,Institutionen för marina vetenskaper,Department of marine sciences(Swepub:gu)xbloan (författare)
Eriksson, Leif A,1964Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xeleif (författare)
Göteborgs universitetInstitutionen för kemi och molekylärbiologi (creator_code:org_t)

Ingår i:Journal of Chemical Information and Modeling: American Chemical Society (ACS)56:9, s. 1776-17861549-95961549-960X

Av författaren/redakt...: Billod, Jean-Mar ...; Saenz Mendez, Pa ...; Blomberg, Anders ...; Eriksson, Leif A ...

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