phosphoserine phosphatase; Phosphoric Monoester Hydrolases; Phosphoric Monoester Hydrolases/metabolism; Catalysis; Mycobacterium tuberculosis/genetics; Mycobacterium tuberculosis/metabolism; Mycobacterium tuberculosis; Medicine (miscellaneous); Biochemistry, Genetics and Molecular Biology (all); Agricultural and Biological Sciences (all); General Agricultural and Biological Sciences; General Biochemistry, Genetics and Molecular Biology
Abstract :
[en] Mycobacterium tuberculosis phosphoserine phosphatase MtSerB2 is of interest as a new antituberculosis target due to its essential metabolic role in L-serine biosynthesis and effector functions in infected cells. Previous works indicated that MtSerB2 is regulated through an oligomeric transition induced by L-Ser that could serve as a basis for the design of selective allosteric inhibitors. However, the mechanism underlying this transition remains highly elusive due to the lack of experimental structural data. Here we describe a structural, biophysical, and enzymological characterisation of MtSerB2 oligomerisation in the presence and absence of L-Ser. We show that MtSerB2 coexists in dimeric, trimeric, and tetrameric forms of different activity levels interconverting through a conformationally flexible monomeric state, which is not observed in two near-identical mycobacterial orthologs. This morpheein behaviour exhibited by MtSerB2 lays the foundation for future allosteric drug discovery and provides a starting point to the understanding of its peculiar multifunctional moonlighting properties.
Research center :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège [BE]
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Pierson, Elise ; Laboratoire de Chimie Biologique Structurale (CBS), Namur Research Institute for Life Sciences (NARILIS), University of Namur (UNamur), 5000, Namur, Belgium
De Pol, Florian; Laboratoire de Chimie Biologique Structurale (CBS), Namur Research Institute for Life Sciences (NARILIS), University of Namur (UNamur), 5000, Namur, Belgium
Fillet, Marianne ; Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Wouters, Johan ; Laboratoire de Chimie Biologique Structurale (CBS), Namur Research Institute for Life Sciences (NARILIS), University of Namur (UNamur), 5000, Namur, Belgium. johan.wouters@unamur.be
Language :
English
Title :
A morpheein equilibrium regulates catalysis in phosphoserine phosphatase SerB2 from Mycobacterium tuberculosis.
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Funding text :
The pAVA0421 plasmids encoding Mt SerB2, Ma SerB and Mm SerB2 were kindly provided by the Seattle Structural Genomics Center for Infectious Disease (www.SSGCID.org) which is supported by Federal Contract No. 75N93022C00036 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. SAXS experiments have been supported by iNEXT-Discovery, grant number 871037, funded by the Horizon 2020 program of the European Commission. We acknowledge SOLEIL for the provision of synchrotron radiation facilities and we would like to thank Dr. J. Pérez and Dr. A. Thureau for assistance in using beamline SWING (proposal number 20210718). We thank Dr. A. Demelenne (LAM, CIRM, ULiège) for her precious help on the SEC-UV-MALS equipment. The Fonds de la Recherche Scientifique (F.R.S.-FNRS, Belgium) is acknowledged for E.P. Research Fellow - ASP grant and for the MALS detector.The pAVA0421 plasmids encoding MtSerB2, MaSerB and MmSerB2 were kindly provided by the Seattle Structural Genomics Center for Infectious Disease ( www.SSGCID.org ) which is supported by Federal Contract No. 75N93022C00036 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. SAXS experiments have been supported by iNEXT-Discovery, grant number 871037, funded by the Horizon 2020 program of the European Commission. We acknowledge SOLEIL for the provision of synchrotron radiation facilities and we would like to thank Dr. J. Pérez and Dr. A. Thureau for assistance in using beamline SWING (proposal number 20210718). We thank Dr. A. Demelenne (LAM, CIRM, ULiège) for her precious help on the SEC-UV-MALS equipment. The Fonds de la Recherche Scientifique (F.R.S.-FNRS, Belgium) is acknowledged for E.P. Research Fellow - ASP grant and for the MALS detector.
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