ArticleJournal of the American Chemical Society2013
Fluoroketone inhibition of Ca(2+)-independent phospholipase A2 through binding pocket association defined by hydrogen/deuterium exchange and molecular dynamics.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 27 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed.
- The mechanism of allosteric regulation of calcium-independent phospholipase AProceedings of the National Academy of Sciences of the United States of America · 2024Article
- The PNPLA family of enzymes: characterisation and biological role.Arhiv za higijenu rada i toksikologiju · 2023Article
- Membrane Association Allosterically Regulates Phospholipase AAccounts of chemical research · 2022Article
- Allosteric regulation by membranes and hydrophobic subsites in phospholipase AThe Journal of biological chemistry · 2022Review
- Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase AJournal of lipid research · 2021Article
- Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases ABiochimica et biophysica acta. Molecular and cell biology of lipids · 2019Review
- Phospholipase ABiochimica et biophysica acta. Molecular and cell biology of lipids · 2019Review
- Article
- β-Lactones: A Novel Class of CaJournal of medicinal chemistry · 2019Article
- Interpreting Hydrogen-Deuterium Exchange Events in Proteins Using Atomistic Simulations: Case Studies on Regulators of G-Protein Signaling Proteins.The journal of physical chemistry. B · 2018Article
- Membrane Allostery and Unique Hydrophobic Sites Promote Enzyme Substrate Specificity.Journal of the American Chemical Society · 2018Article
- The structure of iPLANature communications · 2018Article
- 2-Oxoamides based on dipeptides as selective calcium-independent phospholipase ABioorganic & medicinal chemistry · 2017Article
- Analyses of Calcium-Independent Phospholipase AMethods in enzymology · 2017Article
- Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease.The Journal of biological chemistry · 2016Review
- Computer-aided drug design guided by hydrogen/deuterium exchange mass spectrometry: A powerful combination for the development of potent and selective inhibitors of Group VIA calcium-independent phospholipase ABioorganic & medicinal chemistry · 2016Article
- Development of Potent and Selective Inhibitors for Group VIA Calcium-Independent Phospholipase A2 Guided by Molecular Dynamics and Structure-Activity Relationships.Journal of medicinal chemistry · 2016Article
- Membrane and inhibitor interactions of intracellular phospholipases A2.Advances in biological regulation · 2016Review
- Calcium-independent phospholipases A2 and their roles in biological processes and diseases.Journal of lipid research · 2015Review
- Homologous ligands accommodated by discrete conformations of a buried cavity.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
Corrections and comments
- Erratum issued
Authors and funding
9 authors.
Funding
Abstract
The mechanism of inhibition of group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)) by fluoroketone (FK) ligands is examined by a combination of deuterium exchange mass spectrometry (DXMS) and molecular dynamics (MD). Models for iPLA(2) were built by homology with the known structure of patatin and equilibrated by extensive MD simulations. Empty pockets were identified during the simulations and studied for their ability to accommodate FK inhibitors. Ligand docking techniques showed that the potent inhibitor 1,1,1,3-tetrafluoro-7-phenylheptan-2-one (PHFK) forms favorable interactions inside an active-site pocket, where it blocks the entrance of phospholipid substrates. The polar fluoroketone headgroup is stabilized by hydrogen bonds with residues Gly486, Gly487, and Ser519. The nonpolar aliphatic chain and aromatic group are stabilized by hydrophobic contacts with Met544, Val548, Phe549, Leu560, and Ala640. The binding mode is supported by DXMS experiments showing an important decrease of deuteration in the contact regions in the presence of the inhibitor. The discovery of the precise binding mode of FK ligands to the iPLA(2) should greatly improve our ability to design new inhibitors with higher potency and selectivity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.