Crystallographic and molecular dynamics simulation analysis of NAD synthetase from methicillin resistant Staphylococcus aureus (MRSA).

Autor: Sultana KN; Department of Biosciences, Manipal University Jaipur, Dehmi Kalan, Off Jaipur-Ajmer Expressway, Jaipur, Rajasthan 303007, India., Kuldeep J; Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India., Siddiqi MI; Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India., Srivastava SK; Department of Biosciences, Manipal University Jaipur, Dehmi Kalan, Off Jaipur-Ajmer Expressway, Jaipur, Rajasthan 303007, India. Electronic address: sandeepkumar.srivastava@jaipur.manipal.edu.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2020 Dec 15; Vol. 165 (Pt B), pp. 2349-2362. Date of Electronic Publication: 2020 Oct 21.
DOI: 10.1016/j.ijbiomac.2020.10.096
Abstrakt: NAD synthetase (NadE) catalyzes the last step in NAD biosynthesis, transforming deamido-NAD + into NAD + by a two-step reaction with co-substrates ATP and amide donor ammonia. In this study, we report the crystal structure of Staphylococcus aureus NAD synthetase enzyme (saNadE) at 2.3 Å resolution. We used this structure to perform molecular dynamics simulations of apo-enzyme, enzyme-substrate (NadE with ATP and NaAD) and enzyme-intermediate complexes (NadE with NaAD-AMP) to investigate key binding interactions and explore the conformational transitions and flexibility of the binding pocket. Our results show large shift of N-terminal region in substrate bound form which is important for ATP binding. Substrates drive the correlated movement of loop regions surrounding it as well as some regions distal to the active site and stabilize them at complex state. Principal component analysis of atomic projections distinguish feasible trajectories to delineate distinct motions in enzyme-substrate to enzyme-intermediate states. Our results suggest mixed binding involving dominant induced fit and conformational selection. MD simulation extracted ensembles of NadE could potentially be utilized for in silico screening and structure based design of more effective Methicillin Resistant Staphylococcus aureus (MRSA) inhibitors.
Competing Interests: Declaration of competing interest No author has an actual or perceived conflict of interest with the contents of this article.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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