ArticlePloS one2025
Mechanistic insights into Alpha-Synuclein binding to P2RX7: A molecular dynamic and docking study.
Article in PloS one, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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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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2 citing papers in PubMed.
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Authors and funding
8 authors.
Funding
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Abstract
Alpha-synucleinopathies, characterized by extracellular alpha-synuclein (αSyn or SNCA) accumulation and aggregation, have been linked to neurological disorders including Parkinson's disease and multiple system atrophy. P2RX7 is a non-selective cationic transmembrane purinergic receptor activated by elevated levels of extracellular ATP, which typically occurs during inflammatory conditions. Activation of P2RX7 by αSyn is implicated in neuronal degeneration, potentially causing pore dilation and increased inflammation. By integrating the data curation, molecular docking, and molecular dynamics (MD) simulations, along with structural analyses, we attempted to elucidate the molecular mechanisms and binding sites for P2RX7-αSyn interaction. We elucidated interactions between P2RX7 and the N-terminal domain (NTD) of αSyn. Utilizing cryo-EM structures of P2RX7 in ATP-bound and unbound states, we assessed αSyn's effect on P2RX7 structural and functional dynamics. Initially, the analyses revealed that αSyn interactomes are mainly involved in mitochondrial functions, while P2RX7 interactors are linked to receptor internalization and calcium transport. Molecular docking with six tools identified that αSyn-NTD fragments preferentially bind to the proximal region of P2RX7's transmembrane domain. Microsecond all atom MD simulations in a POPS lipid bilayer showed significant atomic fluctuations, particularly in the head region, lower body, and large loop of P2RX7's cytoplasmic domain. Secondary structure analysis indicated unfolding in regions related to pore dilation and receptor desensitization. Further by contact-based and solvent accessibility analyses, along with protein structure network (PSN) studies, we identified crucial residues involved in αSyn-P2RX7 interactions. This understanding enhances the knowledge of how αSyn and P2RX7 interactions take place, potentially contributing to neurodegenerative diseases, and could be instrumental in developing future preventive and therapeutic approaches.
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