Ronen Marmorstein, Ph.D.

Professor and Program Leader
Gene Expression and Regulation Program
215-898-5006, Office
215-898-0381, Fax

Introduction

The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered around X-ray crystal structure determination to understand the mechanism of chromatin recognition and assembly; post-translational histone and protein modification in the regulation of gene expression; and kinase signaling pathways.  Our laboratory is particularly interested in gene regulatory proteins and their upstream signaling kinases that are aberrantly regulated in cancer and age-related metabolic disorders such as type II diabetes and obesity, and the use of high-throughput small molecule screening and structure-based design strategies towards the development of protein-specific small-molecule probes to be used to further interrogate protein function, and for development into therapeutic agents.

Research Summary

Chromatin recognition and assembly and histone modification in gene regulation. DNA within the eukaryotic nucleus is compacted into chromatin- containing histone proteins. Its appropriate regulation orchestrates all DNA-templated reactions such as DNA transcription, replication, repair, mitosis, and apoptosis.  Among the many proteins that regulate chromatin, those that recognize DNA, assemble chromatin (histone chaperones) and that modify the histones through the addition or removal of functional groups such as acetyl, methyl or phosphate, play important roles.  We are studying the DNA binding proteins p53, FoxO and the Gal4 family; the histone chaperones HIRA, Asf1, Vps75 and their associated factors; and the family of histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes.  We are particularly interested in how DNA binding proteins navigate the recognition of their cognate DNA targets, how histone chaperones coordinate the assembly of distinct chromatin complexes correlated with different DNA regulatory processes, and how histone modification enzymes link catalysis to their substrate specific activities for their respective biological activities.  More recently, we have been studying how the binding of accessory and regulatory protein subunits regulates the various activities of these proteins and in some cases we are developing small molecule protein specific inhibitors.

Enzymes associated with aging and age-related disorders. Sirtuin enzymes are NAD+-dependent histone and protein deactylases and/or ADP-ribotransferases that have been implicated in the regulation of gene expression, cellular aging, adipogenesis, type II diabetes and several neurodegenerative disorders.  We have determined the structure of these enzymes in several liganded forms and have developed novel small molecule sirtuin inhibitors.  Together with associated biochemical studies, these studies have provided insights into the mode of catalysis and substrate-specific recognition by this protein family and have illuminated new avenues for small molecule effector design.  Currently, we are working towards understanding the factors that distinguish different sirtuin proteins and how the functions of these proteins are modulated by other protein factors. We are also pursuing structure/function studies of other proteins that are implicated in aging and age-related disorders.

Tumor suppressors and oncoproteins. We are carrying out biochemical and structural studies on the tumor suppressor proteins pRb, p53 and p300/CBP, both alone and in complex with their relevant protein targets.  We are interested in the mode of inactivation of these tumor suppressors by the viral oncoproteins E7 and E6 from human papillomavirus (HPV), the etiological agent for cervical cancer, and Adenovirus (Ad) E1A.  We are combining structural studies with small molecule screening to prepare small molecule HPV-E7 and HPV-E6 inhibitors.  Most recently we have begun to exploit structure-based design strategies to develop inhibitors of oncogenic kinases, such as PI3K, BRAF and PAK1 implicated in melanoma and other cancers. Our goal for these studies is to derive functional and structural information that will lead to the design of small molecule compounds that may have therapeutic applications.

Selected Publications

Liu, X., Wang, L., Zhao, K., Thompson, P.R. Hwang, Y., Marmorstein, R. and Cole, P.A. The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature. 2008 Feb 14; 451(7180):846-50. 18273021

Tang, Y., Holbert, M.A., Wurtele, H., Meeth, K., Rocha, W., Gharib, M., Jiang, E., Thibault, P., Verreault, A., Cole, P.A. and Marmorstein, R. Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP. Nature Structural & Molecular Biology. 2008 Jul;15(7):738-45. [E-pub 2008 Jun 22] Correction to author's name: 2008 Sep;15(9):998. 18568037

Tang, Y., Meeth, K., Jiang, E., Luo, C. and Marmorstein, R. Structure of Vps75 and implications for histone chaperone function. Proceedings of the National Academy of the Sciences, USA. 2008 August 26; 105(34):12206-11. [E-pub 2008 August 22] 18723682

Maksimoska, J., Li, F., Harms, K., Yi, C., Kissil, J., Marmorstein, R. And Meggers, E. Targeting large kinase active sites with rigid, bulky octahedral ruthenium complexes. Journal of the American Chemical Society. 2008 Oct 31;130(47):15764-15765.[Epub ahead of print] 18973295

Brent, M.M., Iwata, A., Carten, J., Zhao, K. and Marmorstein, R. Structure and biochemical characterization of protein acetyltransferase (PAT) from Sulfolobus Solfataricus. Journal of Biological Chemistry. 2009 Jul 17;284(29):19412-9. [Epub 2009 May 27] 19473964

Hait, N.C., Allegood, J.,Maceyka, M., Strub,G.M., Harikumar, K.B., Singh, S.K., Luo, C., Marmorstein, R., Kordula, T., Milstien, S. and Spiegel, S. Regulation of Histone Acetylation in the Nucleus by Sphingosine-1-Phosphate. Science. 2009 Sep 4;325(5945):1254-7. 19729656

Sanders, B.D., Jackson, B., Brent, M., Taylor, A.M., Dang, W., Berger. S.L., Schreiber, S.L., Howitz. K and Marmorstein, R., Identification and characterization of novel sirtuin inhibitor scaffolds. Bioorganic & Medicinal Chemistry. 2009 Oct 1;17(19):7031-41. [Epub 2009 Aug 3] 19734050