Exploring the binding sites of Staphylococcus aureus phenylalanine tRNA synthetase: A homology model approach

Elbaramawi, Samar S., Ibrahim, Samy M., Lashine, El-Sayed M., El-Sadek, Mohamed E., Mantzourani, Efi ORCID: https://orcid.org/0000-0002-6313-1409 and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2017. Exploring the binding sites of Staphylococcus aureus phenylalanine tRNA synthetase: A homology model approach. Journal of Molecular Graphics and Modelling 73 , pp. 36-47. 10.1016/j.jmgm.2017.02.002

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Abstract

Increased resistance of MRSA (multidrug resistance Staphylococcus aureus) to anti-infective drugs is a threat to global health necessitating the development of anti-infectives with novel mechanisms of action. Phenylalanine tRNA synthetase (PheRS) is a unique enzyme of the aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes for protein biosynthesis. PheRS is an (αb)2 tetrameric enzyme composed of two alpha subunits (PheS) and two larger beta subunits (PheT). Our potential target in the drug development for the treatment of MRSA infections is the phenylalanine tRNA synthetase alpha subunit that contains the binding site for the natural substrate. There is no crystal structure available for S. aureus PheRS, therefore comparative structure modeling is required to establish a putative 3D structure for the required enzyme enabling development of new inhibitors with greater selectivity. The S. aureus PheRS alpha subunit homology model was constructed using Molecular Operating Environment (MOE) software. Staphylococcus haemolyticus PheRS was the main template while Thermus thermophilus PheRS was utilised to predict the enzyme binding with tRNAphe. The model has been evaluated and compared with the main template through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). The query protein active site was predicted from its sequence using a conservation analysis tool. Docking suitable ligands using MOE into the constructed model were used to assess the predicted active sites. The docked ligands involved the PheRS natural substrate (phenylalanine), phenylalanyl-adenylate and several described S. aureus PheRS inhibitors.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	Elsevier
ISSN:	1093-3263
Date of First Compliant Deposit:	24 July 2017
Date of Acceptance:	2 February 2017
Last Modified:	23 Sep 2023 16:50
URI:	https://orca.cardiff.ac.uk/id/eprint/102858

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