Our laboratory uses a combination of structural and biochemical approaches to study the structures, mechanisms, and substrate specificities of a variety of enzymes, with a particular focus on histone modifying enzymes.

1. Structural and Functional Studies of Histone Modifications: Histone modifying enzymes establish and maintain chromatin modifications states that play fundamental roles in governing transcription, DNA damage response, epigenetic gene regulation, and other genomic processes. Our laboratory has characterized the molecular determinants of the substrate specificities of several human histone modifying enzymes, including histone lysine methyltransferases and demethylases, employing structural and biochemical approaches. More recently, we have initiated a new research program aimed at understanding the functions of histone modifying enzymes expressed by bacterial pathogens. Theses enzymes are secreted by the pathogens into host cells where they enter the nucleus and hijack host gene expression by altering histone modifications, thus promoting bacterial replication. Structural and functional characterization of these enzymes from various bacterial pathogens, including Legionella pneumophila, the primary causative agent of Legionnaires’ Disease, is yielding novel insights the molecular basis of their unique histone substrate specificities. Together, these studies are illuminating new aspects of host-pathogen interactions and represent an emerging area of research at the interface of chromatin biology and microbiology.

2. Mechanisms of AdoMet-dependent Methyltransferases: S-adenosylmethionine (AdoMet)-dependent methyltransferases methylate a diverse array of biological substrates, including proteins, nucleic acids, carbohydrates, lipids, cofactors, and hormones. Structural surveys of methyltransferases bound to AdoMet have revealed that the AdoMet methyl sulfonium cation engages in several types of unconventional non-bonded interactions, including methyl carbon-oxygen (CH---O) hydrogen bonding, sulfur chalcogen bonding, and methyl carbon tetrel bonding. The discovery of these unconventional bonds between the AdoMet methyl sulfonium cation and residues and ligands in methyltransferase active sites implicates these interactions in AdoMet binding and the SN2 reaction catalyzed by these enzymes. Using a model lysine methyltransferase and non-reactive lysine analogs, we are investigating the functional importance of these interactions in substrate recognition and catalysis using an interdisciplinary approach combining biochemistry, structural biology, spectroscopy, and computational chemistry. Collectively, these studies are elucidating the mechanisms by which CH---O hydrogen bonding, chalcogen bonding, and tetrel bonding promote AdoMet binding and catalysis in methyltransferases.