Sulfonation of glycopeptide antibiotics by sulfotransferase StaL depends on conformational flexibility of aglycone scaffold

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DOIResolve DOI: http://doi.org/10.1073/pnas.1205377109
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TypeArticle
Journal titlePNAS (Proceedings of the National Academy of Sciences of the United States of America)
ISSN1091-6490
Volume109
Issue29
Pages1182411829; # of pages: 6
Subjectsubstrate binding; substrate flexibility; substrate recognition
AbstractAlthough glycopeptide antibiotics (GPAs), including vancomycin and teicoplanin, represent the most important class of antiinfective agents in the treatment of serious Gram-positive bacterial infections, their usefulness is threatened by the emergence of resistant strains. GPAs are complex natural products consisting of a heptapeptide skeleton assembled via nonribosomal peptide synthesis and constrained through multiple crosslinks, with diversity resulting from enzymatic modifications by a variety of tailoring enzymes, which can be used to produce GPA analogues that could overcome antibiotic resistance. GPA-modifying sulfotransferases are promising tools for generating the unique derivatives. Despite significant sequence and structural similarities, these sulfotransferases modify distinct side chains on the GPA scaffold. To provide insight into the spatial diversity of modifications, we have determined the crystal structure of the ternary complex of bacterial sulfotransferase StaL with the cofactor product 3′-phosphoadenosine 5′-phosphate and desulfo-A47934 aglycone substrate. Desulfo-A47934 binds with the hydroxyl group on the 4-hydroxyphenylglycine in residue 1 directed toward the 3′-phosphoadenosine 5′-phosphate and hydrogen-bonded to the catalytic His67. Homodimeric StaL can accommodate GPA substrate in only one of the two active sites because of potential steric clashes. Importantly, the aglycone substrate demonstrates a flattened conformation, in contrast to the cup-shaped structures observed previously. Analysis of the conformations of this scaffold showed that despite the apparent rigidity due to crosslinking between the side chains, the aglycone scaffold displays substantial flexibility, important for enzymatic modifications by the GPA-tailoring enzymes. We also discuss the potential of using the current structural information in generating unique GPA derivatives.
Publication date
PublisherNational Academy of Science
LanguageEnglish
AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
NRC number53175
NPARC number21268239
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Record identifier49c90450-1d77-4423-98ab-fb18aadc2447
Record created2013-06-07
Record modified2016-05-09
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