Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.

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 mineralizatio...

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Autores principales:	Mohammad Jakir Hosen, Abdullah Zubaer, Simrika Thapa, Bijendra Khadka, Anne De Paepe, Olivier M Vanakker
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b91c3f93c4b74c9ea39afdb5574a1b47
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spelling	oai:doaj.org-article:b91c3f93c4b74c9ea39afdb5574a1b472021-11-25T06:07:04ZMolecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.1932-620310.1371/journal.pone.0102779https://doaj.org/article/b91c3f93c4b74c9ea39afdb5574a1b472014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25062064/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Mohammad Jakir HosenAbdullah ZubaerSimrika ThapaBijendra KhadkaAnne De PaepeOlivier M VanakkerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e102779 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mohammad Jakir Hosen Abdullah Zubaer Simrika Thapa Bijendra Khadka Anne De Paepe Olivier M Vanakker Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.
description	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.
format	article
author	Mohammad Jakir Hosen Abdullah Zubaer Simrika Thapa Bijendra Khadka Anne De Paepe Olivier M Vanakker
author_facet	Mohammad Jakir Hosen Abdullah Zubaer Simrika Thapa Bijendra Khadka Anne De Paepe Olivier M Vanakker
author_sort	Mohammad Jakir Hosen
title	Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.
title_short	Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.
title_full	Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.
title_fullStr	Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.
title_full_unstemmed	Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.
title_sort	molecular docking simulations provide insights in the substrate binding sites and possible substrates of the abcc6 transporter.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/b91c3f93c4b74c9ea39afdb5574a1b47
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Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.

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