How cholesteryl ester transfer protein can also be a potential triglyceride transporter

Abstract CETP transfers cholesteryl esters (CEs) and triglycerides (TGs) between different lipoproteins and came in limelight as a drug-target against CVD. In the search for detailed mechanism of lipid transfer through CETP, enormous effort is devoted employing crystallographic, cryo-EM, and Molecul...

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Autores principales:	Venkat R. Chirasani, Sanjib Senapati
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/34c88ccce26d4bcaa3ba5daa0c454db1
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spelling	oai:doaj.org-article:34c88ccce26d4bcaa3ba5daa0c454db12021-12-02T15:06:02ZHow cholesteryl ester transfer protein can also be a potential triglyceride transporter10.1038/s41598-017-05449-z2045-2322https://doaj.org/article/34c88ccce26d4bcaa3ba5daa0c454db12017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05449-zhttps://doaj.org/toc/2045-2322Abstract CETP transfers cholesteryl esters (CEs) and triglycerides (TGs) between different lipoproteins and came in limelight as a drug-target against CVD. In the search for detailed mechanism of lipid transfer through CETP, enormous effort is devoted employing crystallographic, cryo-EM, and Molecular Dynamics (MD) studies. However, these studies primarily focused on CE-bound CETP structure and CE transfer mechanism. With the reported correlation that CETP looses significant CE transfer activity upon inhibiting TG transfer, it is of tremendous importance to understand the structure and dynamics of TG-bound CETP. Our results from large-scale all-atom and coarse-grained MD simulations show that CETP can accommodate two TG molecules in parallel N-N orientation with TG oleate chains majorly attaining the tuning-fork conformation. In TG-bound form, CETP not only maintained its secondary structures but also exhibited similar bending-twisting motions as reported for CE-CETP crystal structure. Obtained structural information are further validated by correlating to available functional data of 2–8 fold slower transfer rate of TG through CETP, where we show that TGs make 20% additional contacts with CETP compared to CEs. Identified CETP residues facilitating TG binding also match very well with reported mutagenesis data. The study could accelerate the drug-designing processes to combat CETP functionality and CVD.Venkat R. ChirasaniSanjib SenapatiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Venkat R. Chirasani Sanjib Senapati How cholesteryl ester transfer protein can also be a potential triglyceride transporter
description	Abstract CETP transfers cholesteryl esters (CEs) and triglycerides (TGs) between different lipoproteins and came in limelight as a drug-target against CVD. In the search for detailed mechanism of lipid transfer through CETP, enormous effort is devoted employing crystallographic, cryo-EM, and Molecular Dynamics (MD) studies. However, these studies primarily focused on CE-bound CETP structure and CE transfer mechanism. With the reported correlation that CETP looses significant CE transfer activity upon inhibiting TG transfer, it is of tremendous importance to understand the structure and dynamics of TG-bound CETP. Our results from large-scale all-atom and coarse-grained MD simulations show that CETP can accommodate two TG molecules in parallel N-N orientation with TG oleate chains majorly attaining the tuning-fork conformation. In TG-bound form, CETP not only maintained its secondary structures but also exhibited similar bending-twisting motions as reported for CE-CETP crystal structure. Obtained structural information are further validated by correlating to available functional data of 2–8 fold slower transfer rate of TG through CETP, where we show that TGs make 20% additional contacts with CETP compared to CEs. Identified CETP residues facilitating TG binding also match very well with reported mutagenesis data. The study could accelerate the drug-designing processes to combat CETP functionality and CVD.
format	article
author	Venkat R. Chirasani Sanjib Senapati
author_facet	Venkat R. Chirasani Sanjib Senapati
author_sort	Venkat R. Chirasani
title	How cholesteryl ester transfer protein can also be a potential triglyceride transporter
title_short	How cholesteryl ester transfer protein can also be a potential triglyceride transporter
title_full	How cholesteryl ester transfer protein can also be a potential triglyceride transporter
title_fullStr	How cholesteryl ester transfer protein can also be a potential triglyceride transporter
title_full_unstemmed	How cholesteryl ester transfer protein can also be a potential triglyceride transporter
title_sort	how cholesteryl ester transfer protein can also be a potential triglyceride transporter
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/34c88ccce26d4bcaa3ba5daa0c454db1
work_keys_str_mv	AT venkatrchirasani howcholesterylestertransferproteincanalsobeapotentialtriglyceridetransporter AT sanjibsenapati howcholesterylestertransferproteincanalsobeapotentialtriglyceridetransporter
_version_	1718388572736716800

How cholesteryl ester transfer protein can also be a potential triglyceride transporter

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