Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region

Abstract The enzyme Pantothenate synthetase (PS) represents a potential drug target in Mycobacterium tuberculosis. Its X-ray crystallographic structure has demonstrated the significance and importance of conserved active site residues including His44, His47, Asn69, Gln72, Lys160 and Gln164 in substr...

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Autores principales: Bharati Pandey, Sonam Grover, Sukriti Goyal, Anchala Kumari, Aditi Singh, Salma Jamal, Jagdeep Kaur, Abhinav Grover
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Publicado: Nature Portfolio 2018
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spelling oai:doaj.org-article:f1cfeaafef314c08819d16b4dfdec2f72021-12-02T15:08:13ZAlanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region10.1038/s41598-017-19075-22045-2322https://doaj.org/article/f1cfeaafef314c08819d16b4dfdec2f72018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-19075-2https://doaj.org/toc/2045-2322Abstract The enzyme Pantothenate synthetase (PS) represents a potential drug target in Mycobacterium tuberculosis. Its X-ray crystallographic structure has demonstrated the significance and importance of conserved active site residues including His44, His47, Asn69, Gln72, Lys160 and Gln164 in substrate binding and formation of pantoyl adenylate intermediate. In the current study, molecular mechanism of decreased affinity of the enzyme for ATP caused by alanine mutations was investigated using molecular dynamics (MD) simulations and free energy calculations. A total of seven systems including wild-type + ATP, H44A + ATP, H47A + ATP, N69A + ATP, Q72A + ATP, K160A + ATP and Q164A + ATP were subjected to 50 ns MD simulations. Docking score, MM-GBSA and interaction profile analysis showed weak interactions between ATP (substrate) and PS (enzyme) in H47A and H160A mutants as compared to wild-type, leading to reduced protein catalytic activity. However, principal component analysis (PCA) and free energy landscape (FEL) analysis revealed that ATP was strongly bound to the catalytic core of the wild-type, limiting its movement to form a stable complex as compared to mutants. The study will give insight about ATP binding to the PS at the atomic level and will facilitate in designing of non-reactive analogue of pantoyl adenylate which will act as a specific inhibitor for PS.Bharati PandeySonam GroverSukriti GoyalAnchala KumariAditi SinghSalma JamalJagdeep KaurAbhinav GroverNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Bharati Pandey
Sonam Grover
Sukriti Goyal
Anchala Kumari
Aditi Singh
Salma Jamal
Jagdeep Kaur
Abhinav Grover
Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region
description Abstract The enzyme Pantothenate synthetase (PS) represents a potential drug target in Mycobacterium tuberculosis. Its X-ray crystallographic structure has demonstrated the significance and importance of conserved active site residues including His44, His47, Asn69, Gln72, Lys160 and Gln164 in substrate binding and formation of pantoyl adenylate intermediate. In the current study, molecular mechanism of decreased affinity of the enzyme for ATP caused by alanine mutations was investigated using molecular dynamics (MD) simulations and free energy calculations. A total of seven systems including wild-type + ATP, H44A + ATP, H47A + ATP, N69A + ATP, Q72A + ATP, K160A + ATP and Q164A + ATP were subjected to 50 ns MD simulations. Docking score, MM-GBSA and interaction profile analysis showed weak interactions between ATP (substrate) and PS (enzyme) in H47A and H160A mutants as compared to wild-type, leading to reduced protein catalytic activity. However, principal component analysis (PCA) and free energy landscape (FEL) analysis revealed that ATP was strongly bound to the catalytic core of the wild-type, limiting its movement to form a stable complex as compared to mutants. The study will give insight about ATP binding to the PS at the atomic level and will facilitate in designing of non-reactive analogue of pantoyl adenylate which will act as a specific inhibitor for PS.
format article
author Bharati Pandey
Sonam Grover
Sukriti Goyal
Anchala Kumari
Aditi Singh
Salma Jamal
Jagdeep Kaur
Abhinav Grover
author_facet Bharati Pandey
Sonam Grover
Sukriti Goyal
Anchala Kumari
Aditi Singh
Salma Jamal
Jagdeep Kaur
Abhinav Grover
author_sort Bharati Pandey
title Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region
title_short Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region
title_full Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region
title_fullStr Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region
title_full_unstemmed Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region
title_sort alanine mutation of the catalytic sites of pantothenate synthetase causes distinct conformational changes in the atp binding region
publisher Nature Portfolio
publishDate 2018
url https://doaj.org/article/f1cfeaafef314c08819d16b4dfdec2f7
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