Dataset Information

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

ABSTRACT: The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound exporter protein involved in regulating serum HDL level by exporting cholesterol and phospholipids to load up in lipid-poor ApoA-I and ApoE, which allows the formation of nascent HDL. Mutations in the ABCA1 gene, when presents in both alleles, disrupt the canonical function of ABCA1, which associates with many disorders related to lipid transport. Although many studies have reported the phenotypic effects of a large number of ABCA1 variants, the pathological effect of non-synonymous polymorphisms (nsSNPs) in ABCA1 remains elusive. Therefore, aiming at exploring the structural and functional consequences of nsSNPs in ABCA1, in this study, we employed an integrated computational approach consisting of nine well-known in silico tools to identify damaging SNPs and molecular dynamics (MD) simulation to get insights into the magnitudes of the damaging effects. In silico tools revealed four nsSNPs as being most deleterious, where the two SNPs (G1050V and S1067C) are identified as the highly conserved and functional disrupting mutations located in the NBD1 domain. MD simulation suggested that both SNPs, G1050V and S1067C, changed the overall structural flexibility and dynamics of NBD1, and induced substantial alteration in the structural organization of ATP binding site. Taken together, these findings direct future studies to get more insights into the role of these variants in the loss of the ABCA1 function.

SUBMITTER: Dash R

PROVIDER: S-EPMC7589834 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

Dash Raju R Ali Md Chayan MC Rana Md Liton ML Munni Yeasmin Akter YA Barua Largess L Jahan Israt I Haque Mst Fatema MF Hannan Md Abdul MA Moon Il Soo IS

International journal of molecular sciences 20201014 20

The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound exporter protein involved in regulating serum HDL level by exporting cholesterol and phospholipids to load up in lipid-poor ApoA-I and ApoE, which allows the formation of nascent HDL. Mutations in the <i>ABCA1</i> gene, when presents in both alleles, disrupt the canonical function of ABCA1, which associates with many disorders related to lipid transport. Although many studies have reported the phenotypic effects of a large numbe ...[more]

PMID: 33066695

Similar Datasets

Project description:Traditional cancer treatment approaches are often hindered by the presence of toxic side effects and the high rate of relapse observed in treated organs. In contrast, novel immunotherapeutic strategies targeting immune checkpoint inhibitors, particularly PD-1, have demonstrated promising results with minimal adverse effects. However, the emergence of immunotherapeutic-resistant tumors, predominantly caused by intrinsic mutations, poses a significant obstacle to successful treatment outcomes. Consequently, the primary objective of this study was to screen for the most detrimental missense mutations in the PD-1 gene associated with immunotherapeutic resistance. To achieve this aim, a comprehensive screening process utilizing 20 web servers, incorporating both sequence- and structure-based methodologies, was undertaken. Through meticulous analysis and mutual disease association sorting, four specific missense mutations were successfully identified. These mutations, namely, R38C, D61V, R94C, and D117V, emerged as the leading contributors to genetic cancer progression and immunotherapeutic resistance against PD-1 blockers. The findings presented in this study are supported by multiple lines of evidence. A thorough examination of protein topology, structural alignment, docking interactions with PD-L1, and protein flexibility collectively confirmed the pathogenic nature of these sorted mutations. By considering these various aspects, we have gained a comprehensive understanding of the underlying mechanisms driving immunotherapeutic resistance. In conclusion, the comprehensive screening process undertaken in this study has successfully identified R38C, D61V, R94C, and D117V as the primary mutations contributing to genetic cancer progression and immunotherapeutic resistance against PD-1 blockers. The integration of protein topology analysis, structural alignment, docking studies with PD-L1, and assessment of protein flexibility have collectively provided robust evidence to support the pathogenic significance of these mutations.

Dataset Information

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

Publications

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets