Raymond Trievel, Ph.D.

Associate Professor, Biological Chemistry

Office: 4301C MSRB III
Lab: 4315 MSRB III
1150 W. Medical Center Drive
Ann Arbor, MI 48109-5606

(734) 647-0889

Areas of Interest

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

Honors & Awards

Margaret C. Etter Early Career Award, American Crystallographic Association, 2010
Basic Science Research Award, University of Michigan Medical School, 2010
NIH Fellowship Award for Research Excellence, 2004
Keystone Symposium Scholarship, 2003
Intramural Research Training Fellowship, National Institutes of Health, 2000–2003
Howard Hughes Medical Institute Predoctoral Fellowship, 1996–2000

Published Articles or Reviews

Recent Publications

Structural and Functional Characterization of Sulfonium Carbon-Oxygen Hydrogen Bonding in the Deoxyamino Sugar Methyltransferase TylM1.
Fick RJ, Horowitz S, McDole BG, Clay MC, Mehl RA, Al-Hashimi HM, Scheiner S, Trievel RC.
Biochemistry. 2019; 58: 2152–9.

Crystallographic and Computational Characterization of Methyl Tetrel Bonding in S-Adenosylmethionine-Dependent Methyltransferases.
Trievel RC, Scheiner S.
Molecules. 2018; 23: 2965.

The structure of human Nocturnin reveals a conserved ribonuclease domain that represses target transcript translation and abundance in cells.
Abshire ET, Chasseur J, Bohn JA, Del Rizzo PA, Freddolino PL, Goldstrohm AC, Trievel RC.
Nucleic Acids Res. 2018; 46: 6257–70.

Water-Mediated Carbon-Oxygen Hydrogen Bonding Facilitates S-Adenosylmethionine Recognition in the Reactivation Domain of Cobalamin-Dependent Methionine Synthase.
Fick RJ, Clay MC, Vander Lee L, Scheiner S, Al-Hashimi H, Trievel RC.
Biochemistry. 2018; 57: 3733–40.

Sulfur-Oxygen Chalcogen Bonding Mediates AdoMet Recognition in the Lysine Methyltransferase SET7/9.
Fick RJ, Kroner GM, Nepal B, Magnani R, Horowitz S, Houtz RL, Scheiner S, Trievel RC.
ACS Chem Biol. 2016; 11: 748–54.

Frequent side chain methyl carbon-oxygen hydrogen bonding in proteins revealed by computational and stereochemical analysis of neutron structures.
Yesselman JD, Horowitz S, Brooks CL 3rd, Trievel RC.
Proteins. 2015; 83: 403–10.

Manipulating unconventional CH-based hydrogen bonding in a methyltransferase via noncanonical amino acid mutagenesis.
Horowitz S, Adhikari U, Dirk LM, Del Rizzo PA, Mehl RA, Houtz RL, Al-Hashimi HM, Scheiner S, Trievel RC.
ACS Chem Biol. 2014; 9: 1692–7.

Conservation and functional importance of carbon-oxygen hydrogen bonding in AdoMet-dependent methyltransferases.
Horowitz S, Dirk LM, Yesselman JD, Nimtz JS, Adhikari U, Mehl RA, Scheiner S, Houtz RL, Al-Hashimi HM, Trievel RC.
J Am Chem Soc. 2013; 135: 15536–48.

Structural and functional analysis of JMJD2D reveals molecular basis for site-specific demethylation among JMJD2 demethylases.
Krishnan S, Trievel RC.
Structure. 2013; 21: 98–108.


Structure, mechanism, and regulation of polycomb-repressive complex 2.
Moritz LE, Trievel RC.
J Biol Chem. 2018; 293: 13805–14.

Molecular basis for substrate recognition by lysine methyltransferases and demethylases.
Del Rizzo PA, Trievel RC.
Biochim Biophys Acta. 2014; 1839: 1404–15.

An overview of chromatin modifications.
Fick RJ, Trievel RC.
Biopolymers. 2013; 99: 95–7.

Carbon-oxygen hydrogen bonding in biological structure and function.
Horowitz S, Trievel RC.
J Biol Chem. 2012; 287: 41576–82.

For a list of publications from PubMed, click HERE

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