Exploring Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Autoproteolysis Process by Molecular Simulations: Hints for Drug Design
Articolo
Data di Pubblicazione:
2020
Citazione:
Exploring Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Autoproteolysis Process by Molecular Simulations: Hints for Drug Design / J. Sgrignani, E.M.A. Fassi, C. Lammi, G. Roda, G. Grazioso. - In: CHEMMEDCHEM. - ISSN 1860-7179. - (2020). [Epub ahead of print] [10.1002/cmdc.202000431]
Abstract:
Proprotein convertase subtilisin/kexin 9 (PCSK9) is a notable target for the treatment of hypercholesterolemia because it regulates the population of the low-density lipoprotein receptor (LDLR) on liver cells. The PCSK9 zymogen is a serine protease that spontaneously undergoes a double self-cleavage step. The available X-ray structures depict the PCSK9 mature state, but the atomic details of the zymogen state of the enzyme are still unknown. Additionally, why the protease activity of PCSK9 is blocked after the second autoprocessing step remains unclear, as this deviates from other members of the PCSK family. By performing constant-pH molecular dynamics (MD) simulations, we investigated the protonation state of the catalytic triad of PCSK9 and found that it strongly influences the catalytic properties of the enzyme. Moreover, we determined the final step of the maturation process by classical and steered MD simulations. This study could facilitate the identification of ligands capable of interfering with the PCSK9 maturation process.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
PCSK9; constant-pH molecular dynamics simulations; drug design; molecular dynamics; pKa prediction
Elenco autori:
J. Sgrignani, E.M.A. Fassi, C. Lammi, G. Roda, G. Grazioso
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