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

1 - Huang R, Holbert MA, Tarrant MK, Curtet S, Colquhoun DR,et al., Marmorstein R, Cole RN, Khochbin S, Cole PA., Site-specific introduction of an acetyl-lysine mimic into peptides and proteins by cysteine alkylation., Journal of the Americab Chemical Society. 2010 Jul 7. [Epub ahead of print], 20608637

2 - Bowers EM, et al., Liszczak G, Yuan H, Larocca C, Saldanha SA, Abagyan R, Sun Y, Meyers DJ, Marmorstein R, et al., Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor., Chemistry & Biology. 2010 May 28;17(5):471-82. Comment in: Chemical Biology. 2010 May 28;17(5):417-8. , 20534345

3 - Yi C, Maksimoska J, Marmorstein R, Kissil JL., Development of small-molecule inhibitors of the group I p21-activated kinases, emerging therapeutic targets in cancer., Biochemical Pharmacology. 2010 Sep 1;80(5):683-689. [Epub 2010 Mar 17] , 20302846

4 - Ipsaro JJ, Harper SL, Messick TE, Marmorstein R, Mondragón A, Speicher DW., Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex., Blood. 2010 Jun 10;115(23):4843-52. [Epub 2010 Mar 2], 20197550

5 - Marmorstein R., Anticipating drug resistance in the MAP kinase pathway., Pigment Cell and Melanoma Research. 2010 Feb;23(1):7-9. [Epub 2009 Dec 2] , 19968818

6 - Sanders BD, Jackson B, Marmorstein R., Structural basis for sirtuin function: What we know and what we don't., Biochimica Biophysica Acta. 2010 Aug;1804(8):1604-1616. [Epub 2009 Sep 18], 19766737

7 - Sanders BD, Jackson B, Brent M, Taylor AM, Dang W, Berger SL, Schreiber SL, Howitz K, 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

8 - Hait NC, Allegood J, Maceyka M et al., Luo C, Marmorstein R, Kordula T, Milstien S, Spiegel S., Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate., Science. 2009 Sep 4;325(5945):1254-7., 19729656

9 - Brent MM, Iwata A, Carten J, Zhao K, 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

10 - Xie P, Streu C, Qin J, Bregman H, Pagano N, Meggers E, Marmorstein R., Crystal structure of BRAF in complex with an organoruthenium inhibitor reveals a mechanism for inhibition of an active form of BRAF kinase., Biochemistry. 2009 Jun 16;48(23):5187-98., 19371126