Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts

Abstract Enzymes sample multiple conformations during their catalytic cycles. Chemical shifts from Nuclear Magnetic Resonance (NMR) are hypersensitive to conformational changes and ensembles in solution. Phosphomannomutase/phosphoglucomutase (PMM/PGM) is a ubiquitous four-domain enzyme that catalyze...

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Autores principales:	Jia Xu, Akella V. S. Sarma, Yirui Wei, Lesa J. Beamer, Steven R. Van Doren
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0fe5ee31f31b4b3f975284ec69edc7f2
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spelling	oai:doaj.org-article:0fe5ee31f31b4b3f975284ec69edc7f22021-12-02T16:07:47ZMultiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts10.1038/s41598-017-05557-w2045-2322https://doaj.org/article/0fe5ee31f31b4b3f975284ec69edc7f22017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05557-whttps://doaj.org/toc/2045-2322Abstract Enzymes sample multiple conformations during their catalytic cycles. Chemical shifts from Nuclear Magnetic Resonance (NMR) are hypersensitive to conformational changes and ensembles in solution. Phosphomannomutase/phosphoglucomutase (PMM/PGM) is a ubiquitous four-domain enzyme that catalyzes phosphoryl transfer across phosphohexose substrates. We compared states the enzyme visits during its catalytic cycle. Collective responses of Pseudomonas PMM/PGM to phosphosugar substrates and inhibitor were assessed using NMR-detected titrations. Affinities were estimated from binding isotherms obtained by principal component analysis (PCA). Relationships among phosphosugar-enzyme associations emerge from PCA comparisons of the titrations. COordiNated Chemical Shifts bEhavior (CONCISE) analysis provides novel discrimination of three ligand-bound states of PMM/PGM harboring a mutation that suppresses activity. Enzyme phosphorylation and phosphosugar binding appear to drive the open dephosphorylated enzyme to the free phosphorylated state, and on toward ligand-closed states. Domain 4 appears central to collective responses to substrate and inhibitor binding. Hydrogen exchange reveals that binding of a substrate analogue enhances folding stability of the domains to a uniform level, establishing a globally unified structure. CONCISE and PCA of NMR spectra have discovered novel states of a well-studied enzyme and appear ready to discriminate other enzyme and ligand binding states.Jia XuAkella V. S. SarmaYirui WeiLesa J. BeamerSteven R. Van DorenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jia Xu Akella V. S. Sarma Yirui Wei Lesa J. Beamer Steven R. Van Doren Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts
description	Abstract Enzymes sample multiple conformations during their catalytic cycles. Chemical shifts from Nuclear Magnetic Resonance (NMR) are hypersensitive to conformational changes and ensembles in solution. Phosphomannomutase/phosphoglucomutase (PMM/PGM) is a ubiquitous four-domain enzyme that catalyzes phosphoryl transfer across phosphohexose substrates. We compared states the enzyme visits during its catalytic cycle. Collective responses of Pseudomonas PMM/PGM to phosphosugar substrates and inhibitor were assessed using NMR-detected titrations. Affinities were estimated from binding isotherms obtained by principal component analysis (PCA). Relationships among phosphosugar-enzyme associations emerge from PCA comparisons of the titrations. COordiNated Chemical Shifts bEhavior (CONCISE) analysis provides novel discrimination of three ligand-bound states of PMM/PGM harboring a mutation that suppresses activity. Enzyme phosphorylation and phosphosugar binding appear to drive the open dephosphorylated enzyme to the free phosphorylated state, and on toward ligand-closed states. Domain 4 appears central to collective responses to substrate and inhibitor binding. Hydrogen exchange reveals that binding of a substrate analogue enhances folding stability of the domains to a uniform level, establishing a globally unified structure. CONCISE and PCA of NMR spectra have discovered novel states of a well-studied enzyme and appear ready to discriminate other enzyme and ligand binding states.
format	article
author	Jia Xu Akella V. S. Sarma Yirui Wei Lesa J. Beamer Steven R. Van Doren
author_facet	Jia Xu Akella V. S. Sarma Yirui Wei Lesa J. Beamer Steven R. Van Doren
author_sort	Jia Xu
title	Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts
title_short	Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts
title_full	Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts
title_fullStr	Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts
title_full_unstemmed	Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts
title_sort	multiple ligand-bound states of a phosphohexomutase revealed by principal component analysis of nmr peak shifts
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0fe5ee31f31b4b3f975284ec69edc7f2
work_keys_str_mv	AT jiaxu multipleligandboundstatesofaphosphohexomutaserevealedbyprincipalcomponentanalysisofnmrpeakshifts AT akellavssarma multipleligandboundstatesofaphosphohexomutaserevealedbyprincipalcomponentanalysisofnmrpeakshifts AT yiruiwei multipleligandboundstatesofaphosphohexomutaserevealedbyprincipalcomponentanalysisofnmrpeakshifts AT lesajbeamer multipleligandboundstatesofaphosphohexomutaserevealedbyprincipalcomponentanalysisofnmrpeakshifts AT stevenrvandoren multipleligandboundstatesofaphosphohexomutaserevealedbyprincipalcomponentanalysisofnmrpeakshifts
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Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts

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