title: Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.
abstract: The human ATP-binding cassette family C member 6 (ABCC6) gene encodes an ABC transporter protein (ABCC6), primarily expressed in liver and kidney. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disease characterized by ectopic mineralization of the elastic fibers. The pathophysiology underlying PXE is incompletely understood, which can at least partly be explained by the undetermined nature of the ABCC6 substrates as well as the unknown substrate recognition and binding sites. Several compounds, including anionic glutathione conjugates (N-ethylmaleimide; NEM-GS) and leukotriene C4 (LTC4) were shown to be modestly transported in vitro; conversely, vitamin K3 (VK3) was demonstrated not to be transported by ABCC6. To predict the possible substrate binding pockets of the ABCC6 transporter, we generated a 3D homology model of ABCC6 in both open and closed conformation, qualified for molecular docking and virtual screening approaches. By docking 10 reported in vitro substrates in our ABCC6 3D homology models, we were able to predict the substrate binding residues of ABCC6. Further, virtual screening of 4651 metabolites from the Human Serum Metabolome Database against our open conformation model disclosed possible substrates for ABCC6, which are mostly lipid and biliary secretion compounds, some of which are found to be involved in mineralization. Docking of these possible substrates in the closed conformation model also showed high affinity. Virtual screening expands this possibility to explore more compounds that can interact with ABCC6, and may aid in understanding the mechanisms leading to PXE.
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet, Bangladesh.
authors: Mohammad Jakir
authors: MJ
authors: Hosen
authors: Swapnojaatra Bioresearch Laboratory, DataSoft Systems, Dhaka, Bangladesh.
authors: Abdullah
authors: A
authors: Zubaer
authors: Swapnojaatra Bioresearch Laboratory, DataSoft Systems, Dhaka, Bangladesh.
authors: Simrika
authors: S
authors: Thapa
authors: Swapnojaatra Bioresearch Laboratory, DataSoft Systems, Dhaka, Bangladesh.
authors: Bijendra
authors: B
authors: Khadka
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Anne
authors: A
authors: De Paepe
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Olivier M
authors: OM
authors: Vanakker
mesh_terms: D001665:Binding Sites; D062126:Databases, Chemical; D006801:Humans; D055442:Metabolome; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000473:pathology; D013379:Substrate Specificity
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human