Dynamics of the personalities of PCSK9 on missense variants (rs505151 and rs562556) from elderly cohort studies in Brazil

Author(s)

Lopes, Vitor Galvao ; de Oliveira, Victor Fernandes ; Dati, Livia Mendonca Munhoz ; Naslavsky, Michel Satya ; Ferreira, Glaucio Monteiro ; Hirata, Mario Hiroyuki

• Document type: Journal article
• Source: JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS; v. N/A, p. 9-pg., 2023-03-25.

Abstract

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptors (LDLR). Gain-of-function (GOF) variants of PCSK9 significantly affects lipid metabolism leading to coronary artery disease (CAD), owing to the raising the plasma low-density lipoprotein (LDL). Considering the public health matter, large-scale genomic studies have been conducted worldwide to provide the genetic architecture of populations for the implementation of precision medicine actions. Nevertheless, despite the advances in genomic studies, non-European populations are still underrepresented in public genomic data banks. Despite this, we found two high-frequency variants (rs505151 and rs562556) in the ABraOM databank (Brazilian genomic variants) from a cohort SABE study conducted in the largest city of Brazil, Sao Paulo. Here, we assessed the structural and dynamical features of these variants against WT through a molecular dynamics study. We sought fundamental dynamical interdomain relations through Perturb Response Scanning (PRS) and we found an interesting change of dynamical relation between prodomain and Cysteine-Histidine-Rich-Domain (CHRD) in the variants. The results highlight the pivotal role of prodomain in the PCSK9 dynamic and the implications for the development of new drugs depending on patient group genotype. (AU)

• FAPESP's process: 21/11205-9 - Development of new drugs based on the structure of essential proteins for cholesterol synthesis and metabolism, integrating genetic studies and molecular modeling of dyslipidemic patients
• Grantee: Glaucio Monteiro Ferreira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/12899-6 - Genomics, epigenomics and pharmacogenomics characterization of familial hypercholesterolemia in the Brazilian population
• Grantee: Mario Hiroyuki Hirata
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/11917-6 - Development of a specific pipeline of bioinformatics
• Grantee: Victor Fernandes de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/06490-3 - Search a new PCSK9 inhibitor using techniques of drug planning based on a target structure
• Grantee: Vitor Galvão Lopes
• Support Opportunities: Scholarships in Brazil - Scientific Initiation