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Title:
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Structure-function features of a mycoplasma glycolipid synthase derived from structural data integration, molecular simulations, and mutational analysis
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Author:
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Planas, Antoni (Planas Sauter); Biarnés Fontal, Xevi; Romero, Javier (Romero García); Francisco, Carles
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Other authors:
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Universitat Ramon Llull. IQS |
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Abstract:
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Glycoglycerolipids are structural components of mycoplasma membranes with a fundamental role in membrane properties and stability. Their biosynthesis is mediated by glycosyltransferases (GT) that catalyze the transfer of glycosyl units from a sugar nucleotide donor to diacylglycerol. The essential function of glycolipid synthases in mycoplasma viability, and the absence of glycoglycerolipids in animal host cells make these GT enzymes a target for drug discovery by designing specific inhibitors. However, rational drug design has been hampered by the lack of structural information for any mycoplasma GT. Most of the annotated GTs in pathogenic mycoplasmas belong to family GT2. We had previously shown that MG517 in Mycoplasma genitalium is a GT-A family GT2 membraneassociated glycolipid synthase. We present here a series of structural models of MG517 obtained by homology modeling following a multiple-template approach. The models have been validated by mutational analysis and refined by long scale molecular dynamics simulations. Based on the models, key structure-function relationships have been identified: The N-terminal GT domain has a GT-A topology that includes a non-conserved variable region involved in acceptor substrate binding. Glu193 is proposed as the catalytic base in the GT mechanism, and Asp40, Tyr126, Tyr169, Ile170 and Tyr218 define the substrates binding site. Mutation Y169F increases the enzyme activity and significantly alters the processivity (or sequential transferase activity) of the enzyme. This is the first structural model of a GT-A glycoglycerolipid synthase and provides preliminary insights into structure and function relationships in this family of enzymes. |
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Publication date:
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2013-12 |
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Subject (UDC):
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577 - Bioquímica. Biologia molecular. Biofísica |
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Subject(s):
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Dinàmica molecular
Proteïnes--Estructura
Micoplasmosis
Enzims
Cristalls
Glucosiltransferases
Sequence alignment
Molecular dynamics
Protein structure
Protein structure comparison
Mycoplasma
Enzyme structure
Crystal structure
Glycosyltransferases |
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Rights:
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L'accés als continguts d'aquest document queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons:http://creativecommons.org/licenses/by/4.0/
© L'autor/a |
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Pages:
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14 p. |
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Document type:
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Article
Article - Published version |
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DOI:
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https://doi.org/10.1371/journal.pone.0081990
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Published by:
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Public Library of Science (PLoS)
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Publish at:
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PLoS One. Vol.8, n.12 (2013), e81990
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Share:
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