Ronen Marmorstein, Ph.D.

faculty photo
George W. Raiziss Professor
Department: Biochemistry and Biophysics

Contact information
BRB II/III, Room 454
421 Curie Blvd.
Philadelphia, PA 19104-6161
Office: (215) 898-7740
Fax: (215) 746-5511
B.S. (Chemistry and Genetics)
University of California, Davis, 1984.
M.S. (Physical Chemistry )
University of Chicago, 1989.
Ph.D. (Chemistry)
University of Chicago, 1989.
Cert. (Mentoring Facilitator For Faculty)
Perelman School of Medicine, 2022.
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Description of Research Expertise

Research Interests
Biochemical, biophysical, X-ray crystallographic and cryo-EM techniques. Age-associated diseases such as cancer, and metabolic and neurodegenerative disorders.

Key words: Epigenetics, chromatin regulation, metabolism, protein acetylation, kinases, oncoproteins, X-ray Crystallography, Cryo-EM, enzymology, structure, biophysics, inhibitor development.

Description of Research
The Marmorstein laboratory studies the molecular mechanisms of (1) protein post- and co-translational protein acetylation and acetyl-CoA metabolism, (2) gene expression and epigenetic regulation, and (3) MAPK signaling. The laboratory uses a broad range of biochemical, biophysical and structural research tools (X-ray crystallography and cryo-EM) to determine macromolecular structure and mechanism of action, with a particular focus on macromolecules that are aberrantly regulated in age-associated diseases such as cancer, and metabolic and neurodegenerative disorders. The laboratory also uses high-throughput small molecule screening and structure-based design strategies to develop protein-specific small-molecule probes to interrogate protein function and for preclinical studies. Specific areas of focus are described below:

Epigenetic regulation
DNA within the eukaryotic nucleus is compacted into chromatin containing histone proteins and its appropriate regulation orchestrates gene expression programs that allow cells with identical genetic information to exhibit different phenotypes. These epigenetic changes are mediated by proteins that recognize DNA and native and modified histones; assemble chromatin called histone chaperones; modify the histones through the addition or removal of functional chemical groups such as acetyl, methyl or phosphate; and non-coding RNA molecules. The laboratory is particularly interested in understanding the molecular mechanism of DNA binding proteins, histone chaperones and histone post-translational modifications enzymes. The laboratory is also studying the molecular links between metabolism and epigenetic regulation.

Protein acetylation and acetyl-CoA metabolism
Thousands of proteins, including histones, are acetylated throughout the cell to regulate diverse biological processes, thus placing acetyltransferases on the same playing field as kinases. Indeed, emerging biochemical and structural data further supports mechanistic and biological links between the two enzyme families. Because of this correlation, the laboratory is studying the broad family of protein acetyltransferases that acetylate lysine side chains (KATs), protein N-termini (NATs) and other substrates. The laboratory is particularly interested in how these enzymes are regulated by protein cofactors to modulate substrate activity and specificity, and how protein acetyltransferases might be targeted by small molecule compounds to create molecular probes and therapeutic compounds. The laboratory is also studying the molecular mechanism of proteins involved in the metabolism of the protein acetyltransferase cofactor, acetyl-CoA, and are developing protein inhibitors in this space for treatment of cancer and metabolic disorders.

MAPK signaling
The laboratory is studying the structure and function of protein kinases and their associated proteins that are aberrantly regulated in melanoma and other cancers. The laboratory is also exploiting this understanding to develop novel small molecule inhibitors as molecular probes and as lead molecules for development to treat various cancers.

Rotation Projects
Rotation Students with an interest in incorporating the techniques of molecular biology, biochemistry, X-ray crystallography, cryo-EM, enzymology and inhibitor development to study areas of interest to the laboratory are encouraged to inquire by e-mail to Dr. Marmorstein to discuss specific rotation projects.

Lab personnel:
Postdoctoral Fellows:
Xin Xu
Samar Mohapatra
Stephano Iglesias

Graduate Students:
Elaine Zhou
Kollin Schultz
Meng Li
Sarah Gardner
Julianna Supplee
Karen Zhang
Athena Zhang
Boyu (Eric) Yin

Research Specialists:
Zhiyuan Zhang
Taining Li

Lab Manager:
Lauren Gardner

Undergraduate Students:
Kevin Huang
Elizabeth Wang

Selected Publications

Gonskikh, Y, Stroute, J, Shen, H, Budinich, K, Pingul, B, Schultz, K, Elashal, H, Marmorstein, R, Shi, J, Liu, KF: Noncatalytic regulation of 18S rRNA methyltransferase DIMT1 in acute myeloid leukemia. Genes Dev 2023.

Deng, S, Gardner, SG, Gottlieb, L, Pan, B, Petersson, EJ, Marmorstein, R: Molecular role of NAA38 in thermostability and catalytic activity of teh human NatC N-terminal acetyltransferase. Structure 2023.

Zhao, Z, Zhou, M, Zemerov, SD, Marmorstein, R, and Dmochowski, IJ : Rational design of a genetically encoded NMR zinc sensor. Chemical Sci 2023.

Wei, X, Schultz, K, Pepper, HL, Megill, E, Vogt, A, Snyder, NW, Marmorstein, R: Allosteric role of the citrate synthethase homology domain of ATP citrate lyase. Nature Comm 2023.

Lyon, GJ, Vedaie, M, Besheim, T, Park, A, Marchi, E, Gottlieb, L, Hsieh, T-C, Klinkhammer, H, Sandomirsky, K, Cheng, H, Starr, LJ, Preddy, I, Tseng, M, Li, Q, Hu, Y, Wang, K, Carvalho, A, Martinez, F, Caro-Llopis, A, Gavin, M, Amble, K, Krawitz , P, Marmorstein, R, Herr-Israel, E: Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome. European J Human Genet 2023.

Pan, B, Gardner, S, Schultz, K, Perez, RM, Deng, S, Shimogawa, M, Sato, K, Rhoades, E, Marmorstein, R, Petersson, EJ: Semi-synthetic CoA--synuclein constructs trap N-terminal acetyltransferase NatB for binding mechanism studies. Chem Soc 2023.

Wei, X, Kixmoeller, K, Baltrusaitis, E, Yang, X, Marmorstein, R: Allosteric role of a structural NADP+ molecule in glucose-6-phosphate dehydrogenase activity. Proc Natl Acad Sci 119: e2119695119, 2022.

Ricketts, MD, Emptage, RP, Blobel, GA and Marmorstein, R: The heme-tegulated inhibitor kinase requires dimerization for heme-sensing activity. J Biol Chem 2022.

Grasso, M, Bond, G., Kim, YJ, Boyd, S, Matson, DM, Valenzuela, S, Tsang, T, Schibrowsky, NA, Alwan, KB, Blackburn, NJ, Burslem, GM, Wittung-Stafshede, P, Winkler, DD, Marmorstein, R, and Brady, DC: The copper chaperone CCS facilitates copper binding by MEK1/2 to promote kinase activation. J Biol Chem 26: 101314, 2021.

Jin, R, Grasso, M, Zhou, M, Marmorstein, R and Baumgart, T: Unfolding mechanisms and conformational stability of teh dimeric endophilin N-BAR domain. ACS Omega 6: 20790, 2021.

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Last updated: 04/18/2024
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