Sulfur-Oxygen Chalcogen Bonding Mediates AdoMet Recognition in the Lysine Methyltransferase SET7/9

Robert J. Fick, Grace M. Kroner, Binod Nepal, Roberta Magnani, Scott Horowitz, Robert L. Houtz, Steve Scheiner, Raymond C. Trievel

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Recent studies have demonstrated that carbon-oxygen (CH⋯O) hydrogen bonds have important roles in S-adenosylmethionine (AdoMet) recognition and catalysis in methyltransferases. Here, we investigate noncovalent interactions that occur between the AdoMet sulfur cation and oxygen atoms in methyltransferase active sites. These interactions represent sulfur-oxygen (S⋯O) chalcogen bonds in which the oxygen atom donates a lone pair of electrons to the σ antibonding orbital of the AdoMet sulfur atom. Structural, biochemical, and computational analyses of an asparagine mutation in the lysine methyltransferase SET7/9 that abolishes AdoMet S⋯O chalcogen bonding reveal that this interaction enhances substrate binding affinity relative to the product S-adenosylhomocysteine. Corroborative quantum mechanical calculations demonstrate that sulfonium systems form strong S⋯O chalcogen bonds relative to their neutral thioether counterparts. An inspection of high-resolution crystal structures reveals the presence of AdoMet S⋯O chalcogen bonding in different classes of methyltransferases, illustrating that these interactions are not limited to SET domain methyltransferases. Together, these results demonstrate that S⋯O chalcogen bonds contribute to AdoMet recognition and can enable methyltransferases to distinguish between substrate and product.

Original languageEnglish
Pages (from-to)748-754
Number of pages7
JournalACS Chemical Biology
Volume11
Issue number3
DOIs
StatePublished - Mar 18 2016

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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