Deciphering the pH-dependent oligomerization of aspartate semialdehyde dehydrogenase from Wolbachia endosymbiont of Brugia malayi: An in vitro and in silico approaches.

Autor: Mathimaran A; Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Karaikudi 630004, Tamil Nadu, India., Nagarajan H; Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Karaikudi 630004, Tamil Nadu, India., Mathimaran A; Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Karaikudi 630004, Tamil Nadu, India., Huang YC; Life Science Group, Scientific Research Division, National Synchrotron Radiation Research Center, Hsinchu, Taiwan., Chen CJ; Life Science Group, Scientific Research Division, National Synchrotron Radiation Research Center, Hsinchu, Taiwan., Vetrivel U; Virology & Biotechnology/Bioinformatics Division, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu 600 031, India., Jeyaraman J; Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Karaikudi 630004, Tamil Nadu, India. Electronic address: jjeyakanthan@alagappauniversity.ac.in.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Sep; Vol. 276 (Pt 2), pp. 133977. Date of Electronic Publication: 2024 Jul 17.
DOI: 10.1016/j.ijbiomac.2024.133977
Abstrakt: The enzyme aspartate semialdehyde dehydrogenase (ASDH) plays a pivotal role in the amino acid biosynthesis pathway, making it an attractive target for the development of new antimicrobial drugs due to its absence in humans. This study aims to investigate the presence of ASDH in the filarial parasite Wolbachia endosymbiont of Brugia malayi (WBm) using both in vitro and in silico approaches. The size exclusion chromatography (SEC) and Native-PAGE analysis demonstrate that WBm-ASDH undergoes pH-dependent oligomerization and dimerization. To gain a deeper understanding of this phenomenon, the modelled monomer and dimer structures were subjected to pH-dependent dynamics simulations in various conditions. The results reveal that residues Val240, Gln161, Thr159, Tyr160, and Trp316 form strong hydrogen bond contacts in the intersurface area to maintain the structure in the dimeric form. Furthermore, the binding of NADP + induces conformational changes, leading to an open or closed conformation in the structure. Importantly, the binding of NADP + does not disturb either the dimerization or oligomerization of the protein, a finding confirmed through both in vitro and in silico analysis. These findings shed light on the structural characteristics of WBm-ASDH and offer valuable insights for the development of new inhibitors specific to WBm, thereby contributing to the development of potential therapies for filarial parasitic infections.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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