Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis

Abstract Tuberculosis is caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb) and remains the leading cause of death by infection world-wide. The Mtb genome encodes a disproportionate number of twenty cytochrome P450 enzymes, of which the essential enzyme cytochrome P450 121A1 (CYP121...

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Autores principales:	Amit Kumar, Christopher S. Campomizzi, Natalie Jay, Shaun Ferguson, Emelie-Jo Scheffler, James Lioi, Chengjian Tu, Jun Qu, Claire Simons, D. Fernando Estrada
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a9d2074e6b3a4b9bbf9546ed2afe7af6
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spelling	oai:doaj.org-article:a9d2074e6b3a4b9bbf9546ed2afe7af62021-12-02T14:12:40ZSurface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis10.1038/s41598-020-79545-y2045-2322https://doaj.org/article/a9d2074e6b3a4b9bbf9546ed2afe7af62021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79545-yhttps://doaj.org/toc/2045-2322Abstract Tuberculosis is caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb) and remains the leading cause of death by infection world-wide. The Mtb genome encodes a disproportionate number of twenty cytochrome P450 enzymes, of which the essential enzyme cytochrome P450 121A1 (CYP121A1) remains a target of drug design efforts. CYP121A1 mediates a phenol coupling reaction of the tyrosine dipeptide cyclo-L-Tyr-L-Tyr (cYY). In this work, a structure and function investigation of dimerization was performed as an overlooked feature of CYP121A1 function. This investigation showed that CYP121A1 dimers form via intermolecular contacts on the distal surface and are mediated by a network of solvent-exposed hydrophobic residues. Disruption of CYP121A1 dimers by site-directed mutagenesis leads to a partial loss of specificity for cYY, resulting in an approximate 75% decrease in catalysis. 19F labeling and nuclear magnetic resonance of the enzyme FG-loop was also combined with protein docking to develop a working model of a functional CYP121A1 dimer. The results obtained suggest that participation of a homodimer interface in substrate selectivity represents a novel paradigm of substrate binding in CYPs, while also providing important mechanistic insight regarding a relevant drug target in the development of novel anti-tuberculosis agents.Amit KumarChristopher S. CampomizziNatalie JayShaun FergusonEmelie-Jo SchefflerJames LioiChengjian TuJun QuClaire SimonsD. Fernando EstradaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amit Kumar Christopher S. Campomizzi Natalie Jay Shaun Ferguson Emelie-Jo Scheffler James Lioi Chengjian Tu Jun Qu Claire Simons D. Fernando Estrada Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis
description	Abstract Tuberculosis is caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb) and remains the leading cause of death by infection world-wide. The Mtb genome encodes a disproportionate number of twenty cytochrome P450 enzymes, of which the essential enzyme cytochrome P450 121A1 (CYP121A1) remains a target of drug design efforts. CYP121A1 mediates a phenol coupling reaction of the tyrosine dipeptide cyclo-L-Tyr-L-Tyr (cYY). In this work, a structure and function investigation of dimerization was performed as an overlooked feature of CYP121A1 function. This investigation showed that CYP121A1 dimers form via intermolecular contacts on the distal surface and are mediated by a network of solvent-exposed hydrophobic residues. Disruption of CYP121A1 dimers by site-directed mutagenesis leads to a partial loss of specificity for cYY, resulting in an approximate 75% decrease in catalysis. 19F labeling and nuclear magnetic resonance of the enzyme FG-loop was also combined with protein docking to develop a working model of a functional CYP121A1 dimer. The results obtained suggest that participation of a homodimer interface in substrate selectivity represents a novel paradigm of substrate binding in CYPs, while also providing important mechanistic insight regarding a relevant drug target in the development of novel anti-tuberculosis agents.
format	article
author	Amit Kumar Christopher S. Campomizzi Natalie Jay Shaun Ferguson Emelie-Jo Scheffler James Lioi Chengjian Tu Jun Qu Claire Simons D. Fernando Estrada
author_facet	Amit Kumar Christopher S. Campomizzi Natalie Jay Shaun Ferguson Emelie-Jo Scheffler James Lioi Chengjian Tu Jun Qu Claire Simons D. Fernando Estrada
author_sort	Amit Kumar
title	Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis
title_short	Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis
title_full	Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis
title_fullStr	Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis
title_full_unstemmed	Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis
title_sort	surface hydrophobics mediate functional dimerization of cyp121a1 of mycobacterium tuberculosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a9d2074e6b3a4b9bbf9546ed2afe7af6
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_version_	1718391803800977408

Surface hydrophobics mediate functional dimerization of CYP121A1 of Mycobacterium tuberculosis

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