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Structural Insights...
Structural Insights into Pseudomonas aeruginosa Exotoxin A-Elongation Factor 2 Interactions: A Molecular Dynamics Study
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- Gholami, Asma (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Göteborgs universitet; Shahid Beheshti University, IRN
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- Minai-Tehrani, D. (författare)
- Shahid Beheshti University, IRN
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- Mahdizadeh, Sayyed Jalil (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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- Saenz Mendez, Patricia (författare)
- Karlstads universitet,Institutionen för ingenjörs- och kemivetenskaper (from 2013)
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- Eriksson, Leif A, 1964 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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(creator_code:org_t)
- 2023-02-20
- 2023
- Engelska.
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 63:5, s. 1578-1591
- Relaterad länk:
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https://doi.org/10.1...
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https://kau.diva-por... (primary) (Raw object)
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Exotoxin A (ETA) is an extracellular secreted toxin and a single-chain polypeptide with A and B fragments that is produced by Pseudomonas aeruginosa. It catalyzes the ADP-ribosylation of a post-translationally modified histidine (diphtha-mide) on eukaryotic elongation factor 2 (eEF2), which results in the inactivation of the latter and the inhibition of protein biosynthesis. Studies show that the imidazole ring of diphthamide plays an important role in the ADP-ribosylation catalyzed by the toxin. In this work, we employ different in silico molecular dynamics (MD) simulation approaches to understand the role of diphthamide versus unmodified histidine in eEF2 on the interaction with ETA. Crystal structures of the eEF2-ETA complexes with three different ligands NAD+, ADP-ribose, and beta TAD were selected and compared in the diphthamide and histidine containing systems. The study shows that NAD+ bound to ETA remains very stable in comparison with other ligands, enabling the transfer of ADP-ribose to the N3 atom of the diphthamide imidazole ring in eEF2 during ribosylation. We also show that unmodified histidine in eEF2 has a negative impact on ETA binding and is not a suitable target for the attachment of ADP-ribose. Analyzing of radius of gyration and COM distances for NAD+, beta TAD, and ADP-ribose complexes revealed that unmodified His affects the structure and destabilizes the complex with all different ligands throughout the MD simulations.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- diphtheria-toxin
- adp-ribosylation
- saccharomyces-cerevisiae
- diphthamide modification
- catalytic mechanism
- transition-state
- biosynthesis
- translation
- protein
- translocation
- Pharmacology & Pharmacy
- Chemistry
- Computer Science
- Kemi
- Materials Science
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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