ArticleScientific reports2018
Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 29 citations in OpenAlex.
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- Dynamozones are the most obvious sign of the evolution of conformational dynamics in HIV-1 protease.Scientific reports · 2023Article
- Calendulaglycoside A showing potential activity against SARS-CoV-2 main protease: Molecular docking, molecular dynamics, and SAR studies.Journal of traditional and complementary medicine · 2022Article
- Investigating the structure-activity relationship of marine natural polyketides as promising SARS-CoV-2 main protease inhibitors.RSC advances · 2021Article
- Molecular Docking and Dynamics Simulation Study ofBiology · 2021Article
- Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.International journal of molecular sciences · 2020Article
- Inhibitors of pantothenate synthetase ofRSC advances · 2020Review
- Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents.Frontiers in cellular and infection microbiology · 2020Review
- Analysis of mutations leading to para-aminosalicylic acid resistance in Mycobacterium tuberculosis.Scientific reports · 2019Article
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8 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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