Site of inhibition of the calcium pump (PMCA1) by triaurinecarboxylic acid

CECILIA SOUTO GUEVARA; DIEGO OBIOL; MARCELO COSTABEL; IRENE C MANGIALAVORI

Córdoba

Congreso; LI Reunión Anual SAB; 2023

Sociedad de Biofísica Argentina

The plasma membrane calcium pump (PMCA) is a transmembrane protein with a crucial role in maintaining intracellular Ca2+ homeostasis. It is composed of ten transmembrane segments and three cytoplasmic domains: A, responsible for Ca2+ binding and release; N, involved in ATP binding; and P, the Phosphorylation site. Triaurinecarboxylic Acid (ATA) is a compound with a multitude of potential biological actions. The primary objective of this study is to identify, through in silico analysis, a potential inhibition site on the PMCA1.To achieve this, the PMCA1 structure was obtained from the Protein Data Bank (PDB: 6A69) and subsequently modeled using the SwissModel automated server. Potential binding sites were predicted using the POCASA program. In parallel, the ATA ligand was generated using the AVOGADRO program, and its topology was parameterized using the SwissParam automated server. Molecular docking using AutoDock Vina in UCSF Chimera was performed for ATA at each predicted binding site. Subsequently, non-covalent interactions were analyzed using the Protein-Ligand Interaction Profiler (PLIP) automatedserver. Finally, molecular dynamics simulations were conducted, starting from the best-scoring molecular docking result. The analysis revealed that ATA-Mg potentially binds to a site located between amino acids 292 to 311 and 340 to 360, which are part of the A domain. This site has the potential to inhibit PMCA1 activity due to its involvement in Ca2+ binding and release, as well as its regulatory influence on the positioning of other domains.