Ronen Marmorstein, Ph.D.

faculty photo
George W. Raiziss Professor
Investigator, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine
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
Education:
B.S. (Chemistry and Genetics)
University of California, Davis, 1984.
Ph.D. (Chemistry)
University of Chicago, 1989.
M.S. (Physical Chemistry )
University of Chicago, 1989.
Post-Graduate Training
Postdoctoral Fellow (advisor: Stephen C. Harrison), Harvard University, 1989-1994.
Permanent link
 
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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:
Dan Ricketts
Austin Vogt
Xuepeng Wei

Predoctoral Students:
Sarah Gardner
Meng Li
Kollin Schultz
Julianna Supplee
Mary Szurgot
Athena Zhang
Karen Zhang
Elaine Zhou

Undergraduate Students:
Renee Barbosa
Kevin Huang

Lab Manager
Shirley Zeng

Selected Publications

Kweon HY, Lee MN, Dorfel M, Seo S, Gottlieb L, PaPazyan T, McTiernan N, Ree R, Bolton D, Garcia A, Flory M, Crain J, Sebold A, Lyons S, Ismail A, Marchi E, Sonn SK, Jeong SJ, Jeon S, Ju S, Conway SJ, Kim T, Kim HS, Lee C, Roh TY, Arnesen T, Marmorstein R, Oh G, Lyon GJ.: Naa12 compensates for Naa10 in mice in the amino-terminal acetylation pathway. Elife 10: e65952, Aug 2021.

Deng Y, Deng S, Ho YH, Gardner SM, Huang Z, Marmorstein R, Huang R.: Novel Bisubstrate Inhibitors for Protein N-Terminal Acetyltransferase D. J Med Chem 64: 8263-8271, Jun 2021.

Deng S, Gottlieb L, Pan B, Supplee J, Wei X, Petersson EJ, Marmorstein R.: Molecular mechanism of N-terminal acetylation by the ternary NatC complex. Structure May 2021.

Ji Z, Clark RF, Bhat V, Matthew Hansen T, Lasko LM, Bromberg KD, Manaves V, Algire M, Martin R, Qiu W, Torrent M, Jakob CG, Liu H, Cole PA, Marmorstein R, Kesicki EA, Lai A, Michaelides MR.: Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases. Bioorg Med Chem Lett 39: 127854, May 2021.

Wolpaw AJ, Bayliss R, Büchel G, Dang CV, Eilers M, Gustafson WC, Hansen GH, Jura N, Knapp S, Lemmon MA, Levens D, Maris JM, Marmorstein R, Metallo SJ, Park JR, Penn LZ, Rape M, Roussel MF, Shokat KM, Tansey WP, Verba KA, Vos SM, Weiss WA, Wolf E, Mossé YP.: Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers. Cancer Res 81: 1627-1632, Apr 2021.

Barbosa R, Acevedo LA, Marmorstein R.: The MEK/ERK Network as a Therapeutic Target in Human Cancer. Mol Cancer Res 2021.

Deng S, Marmorstein R.: Protein N-Terminal Acetylation: Structural Basis, Mechanism, Versatility, and Regulation. Trends Biochem Sci 2021.

Wei X, Marmorstein R.: Reply to: Acetyl-CoA is produced by the citrate synthase homology module of ATP-citrate lyase. Nat Struct Mol Biol 2021.

Nguyen D, Lin LY, Zhou JO, Kibby E, Sia TW, Tillis TD, Vapuryan N, Xu MR, Potluri R, Shin Y, Erler EA, Bronkema N, Boehlmer DJ, Chung CD, Burkhard C, Zeng SH, Grasso M, Acevedo LA, Marmorstein R, Fera D.: Identification and Characterization of a B-Raf Kinase α-Helix Critical for the Activity of MEK Kinase in MAPK Signaling. Biochemistry 59: 4755-4765, Dec 2020.

Deng S, Pan B, Gottlieb L, Petersson EJ, Marmorstein R.: Molecular basis for N-terminal alpha-synuclein acetylation by human NatB. Elife 9: e57491, Sep 2020.

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Last updated: 08/17/2021
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