Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.

In humans, type 1 11β-hydroxysteroid dehydrogenase (11β-HSD-1) plays a key role in the regulation of the glucocorticoids balance by converting the inactive hormone cortisone into cortisol. Numerous functional aspects of 11β-HSD-1 have been understood thanks to the availability at the Worldwide Prote...

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Autores principales:	Angelo D Favia, Matteo Masetti, Maurizio Recanatini, Andrea Cavalli
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a37f9e5f4ae7443a97cfe66ddebd9555
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spelling	oai:doaj.org-article:a37f9e5f4ae7443a97cfe66ddebd95552021-11-04T06:07:52ZSubstrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.1932-620310.1371/journal.pone.0025375https://doaj.org/article/a37f9e5f4ae7443a97cfe66ddebd95552011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21966510/?tool=EBIhttps://doaj.org/toc/1932-6203In humans, type 1 11β-hydroxysteroid dehydrogenase (11β-HSD-1) plays a key role in the regulation of the glucocorticoids balance by converting the inactive hormone cortisone into cortisol. Numerous functional aspects of 11β-HSD-1 have been understood thanks to the availability at the Worldwide Protein Data Bank of a number of X-ray structures of the enzyme either alone or in complex with inhibitors, and to several experimental data. However at present, a complete description of the dynamic behaviour of 11β-HSD-1 upon substrate binding is missing. To this aim we firstly docked cortisone into the catalytic site of 11β-HSD-1 (both wild type and Y177A mutant), and then we used steered molecular dynamics and metadynamics to simulate its undocking. This methodology helped shedding light at molecular level on the complex relationship between the enzyme and its natural substrate. In particular, the work highlights a) the reason behind the functional dimerisation of 11β-HSD-1, b) the key role of Y177 in the cortisone binding event, c) the fine tuning of the active site degree of solvation, and d) the role of the S228-P237 loop in ligand recognition.Angelo D FaviaMatteo MasettiMaurizio RecanatiniAndrea CavalliPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e25375 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Angelo D Favia Matteo Masetti Maurizio Recanatini Andrea Cavalli Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.
description	In humans, type 1 11β-hydroxysteroid dehydrogenase (11β-HSD-1) plays a key role in the regulation of the glucocorticoids balance by converting the inactive hormone cortisone into cortisol. Numerous functional aspects of 11β-HSD-1 have been understood thanks to the availability at the Worldwide Protein Data Bank of a number of X-ray structures of the enzyme either alone or in complex with inhibitors, and to several experimental data. However at present, a complete description of the dynamic behaviour of 11β-HSD-1 upon substrate binding is missing. To this aim we firstly docked cortisone into the catalytic site of 11β-HSD-1 (both wild type and Y177A mutant), and then we used steered molecular dynamics and metadynamics to simulate its undocking. This methodology helped shedding light at molecular level on the complex relationship between the enzyme and its natural substrate. In particular, the work highlights a) the reason behind the functional dimerisation of 11β-HSD-1, b) the key role of Y177 in the cortisone binding event, c) the fine tuning of the active site degree of solvation, and d) the role of the S228-P237 loop in ligand recognition.
format	article
author	Angelo D Favia Matteo Masetti Maurizio Recanatini Andrea Cavalli
author_facet	Angelo D Favia Matteo Masetti Maurizio Recanatini Andrea Cavalli
author_sort	Angelo D Favia
title	Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.
title_short	Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.
title_full	Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.
title_fullStr	Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.
title_full_unstemmed	Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.
title_sort	substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/a37f9e5f4ae7443a97cfe66ddebd9555
work_keys_str_mv	AT angelodfavia substratebindingprocessandmechanisticfunctioningoftype111bhydroxysteroiddehydrogenasefromenhancedsamplingmethods AT matteomasetti substratebindingprocessandmechanisticfunctioningoftype111bhydroxysteroiddehydrogenasefromenhancedsamplingmethods AT mauriziorecanatini substratebindingprocessandmechanisticfunctioningoftype111bhydroxysteroiddehydrogenasefromenhancedsamplingmethods AT andreacavalli substratebindingprocessandmechanisticfunctioningoftype111bhydroxysteroiddehydrogenasefromenhancedsamplingmethods
_version_	1718445167123365888

Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods.

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