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Antioxidants
Volume 13
Issue 1
10.3390/antiox13010015
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Article

Distinct or Overlapping Areas of Mitochondrial Thioredoxin 2 May Be Used for Its Covalent and Strong Non-Covalent Interactions with Protein Ligands

by
Charalampos Ntallis
1,
Haralampos Tzoupis
1,
Theodore Tselios
1,
Christos T. Chasapis
2 and
Alexios Vlamis-Gardikas
1,*
1
Department of Chemistry, University of Patras, 26504 Rion, Greece
2
Institute of Chemical Biology, National Hellenic Research Foundation, Vas. Constantinou 48, 11635 Athens, Greece
*
Author to whom correspondence should be addressed.
Antioxidants 2024, 13(1), 15; https://doi.org/10.3390/antiox13010015
Submission received: 1 November 2023 / Revised: 9 December 2023 / Accepted: 16 December 2023 / Published: 20 December 2023
(This article belongs to the Special Issue Interactions of Redox-Active Proteins and Their Substrates)
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Abstract

In silico approaches were employed to examine the characteristics of interactions between human mitochondrial thioredoxin 2 (HsTrx2) and its 38 previously identified mitochondrial protein ligands. All interactions appeared driven mainly by electrostatic forces. The statistically significant residues of HsTrx2 for interactions were characterized as “contact hot spots”. Since these were identical/adjacent to putative thermodynamic hot spots, an energy network approach identified their neighbors to highlight possible contact interfaces. Three distinct areas for binding emerged: (i) one around the active site for covalent interactions, (ii) another antipodal to the active site for strong non-covalent interactions, and (iii) a third area involved in both kinds of interactions. The contact interfaces of HsTrx2 were projected as respective interfaces for Escherichia coli Trx1 (EcoTrx1), 2, and HsTrx1. Comparison of the interfaces and contact hot spots of HsTrx2 to the contact residues of EcoTx1 and HsTrx1 from existing crystal complexes with protein ligands supported the hypothesis, except for a part of the cleft/groove adjacent to Trp30 preceding the active site. The outcomes of this study raise the possibility for the rational design of selective inhibitors for the interactions of HsTrx2 with specific protein ligands without affecting the entirety of the functions of the Trx system.
Keywords: thioredoxin; mitochondria; hot spots; contact area; interface; molecular recognition thioredoxin; mitochondria; hot spots; contact area; interface; molecular recognition
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MDPI and ACS Style

Ntallis, C.; Tzoupis, H.; Tselios, T.; Chasapis, C.T.; Vlamis-Gardikas, A. Distinct or Overlapping Areas of Mitochondrial Thioredoxin 2 May Be Used for Its Covalent and Strong Non-Covalent Interactions with Protein Ligands. Antioxidants 2024, 13, 15. https://doi.org/10.3390/antiox13010015

AMA Style

Ntallis C, Tzoupis H, Tselios T, Chasapis CT, Vlamis-Gardikas A. Distinct or Overlapping Areas of Mitochondrial Thioredoxin 2 May Be Used for Its Covalent and Strong Non-Covalent Interactions with Protein Ligands. Antioxidants. 2024; 13(1):15. https://doi.org/10.3390/antiox13010015

Chicago/Turabian Style

Ntallis, Charalampos, Haralampos Tzoupis, Theodore Tselios, Christos T. Chasapis, and Alexios Vlamis-Gardikas. 2024. "Distinct or Overlapping Areas of Mitochondrial Thioredoxin 2 May Be Used for Its Covalent and Strong Non-Covalent Interactions with Protein Ligands" Antioxidants 13, no. 1: 15. https://doi.org/10.3390/antiox13010015

APA Style

Ntallis, C., Tzoupis, H., Tselios, T., Chasapis, C. T., & Vlamis-Gardikas, A. (2024). Distinct or Overlapping Areas of Mitochondrial Thioredoxin 2 May Be Used for Its Covalent and Strong Non-Covalent Interactions with Protein Ligands. Antioxidants, 13(1), 15. https://doi.org/10.3390/antiox13010015

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