Raymond Trievel, Ph.D.

The Trievel laboratory uses a combination of biochemical and biophysical approaches to study the structures, mechanisms, and substrate specificities of a variety of enzymes, particularly lysine methyltransferases. Current projects include:

Structural and Functional Studies of Histone Methylation. Histone lysine methyltransferases (KMTs) and lysine demethylases (KDMs) establish and maintain chromatin methylation states that play a fundamental role in regulating transcription and other genomic processes. Our laboratory has characterized the molecular determinants of the substrate specificities of several human KMTs and KDMs utilizing crystallographic and biochemical methods. More recently, we have initiated a new research program aimed at understanding the functions of KMTs expressed by bacterial pathogens. Theses enzymes are secreted by the pathogens into host cells where they enter the nucleus and catalyze histone lysine methylation, hijacking host gene expression to promote bacterial replication. Structural and functional characterization of KMTs from Legionella pneumophila, the primary causative agent of Legionnaires’ Disease, is yielding new insights into the molecular basis of their unique histone lysine specificity. 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.

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 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.

Graduate Program Affiliations

Biological Chemistry Graduate Program
Biophysics Graduate Program
Cellular Biotechnology Training Program
Cellular & Molecular Biology Program
Chemical Biology Doctoral Program
Chemical Biology Interface Training Program