Chemical Biology Discussion Group Year-End Symposium

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for Members

Chemical Biology Discussion Group Year-End Symposium

Wednesday, June 6, 2012

The New York Academy of Sciences

Presented By

 

Chemical biology is a diverse and dynamic field involving chemical approaches to studying and manipulating biological systems. The goal of the Academy's Chemical Biology Discussion Group meetings is to enhance interactions among local-area laboratories working in chemical biology and to feature forefront research in chemical biology to the wider community. The meeting traditionally covers a range of current topics in chemical biology, including chemical probe development, organic synthesis, biosynthesis, protein engineering, nanotechnology, and drug discovery. The annual year-end meeting features distinguished keynote speaker Professor Tom Muir of Princeton University. This will be followed by shorter, cutting-edge talks by graduate students and postdoctoral fellows selected from participating NYC-area institutions.

Registration Pricing

Member$0
Student / Postdoc / Fellow Member$0
Nonmember$30
Student / Postdoc / Fellow Nonmember$15


The Chemical Biology Discussion Group is proudly sponsored by




Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation times are subject to change.


Wednesday June 6, 2012

12:30 PM

Registration

1:00 PM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Elizabeth Boon, PhD, Stony Brook University

1:10 PM

C-Peptide Inhibition of Ebola Virus
Chelsea Higgins, Lai lab, Albert Einstein College of Medicine

1:30 PM

Reiterative Recombination for Pathway Engineering: From Yeast to Stem Cells
Miguel Jimenez, Cornish lab, Columbia University

1:50 PM

Metabolic and Enzymatic Characterization of the Intracellular Growth Operon in Mycobacterium tuberculosis
Suzanne T. Thomas, Sampson lab, Stony Brook University

2:10 PM

Chemical Genetics uncovers Cyclin-Dependent Kinase Control of the Initiation-to-Elongation Switch of RNA Polymerase II in Human Cells
Stéphane Larochelle, PhD, Fisher lab, Mount Sinai School of Medicine

2:30 PM

Coffee Break and Poster Session

3:30 PM

Biomimetic Diversity-Oriented Synthesis of Benzannulated Medium Rings by Oxidative Dearomatization/Ring-Expanding Rearomatization
Todd A. Wenderski, PhD, Tan lab, Memorial Sloan-Kettering Cancer Center

3:50 PM

Terebrids Can Do it Too: Discovery and Characterization of a Novel Peptide Neurotoxin Tv1 from Venomous Marine Snail Terebra variegata Active on Nicotinic Receptors
Prachi Anand, PhD, Holford lab, Hunter College, CUNY and The American Museum of Natural History

4:10 PM

Keynote presentation: Chromatin: An Expansive Canvas for Chemical Biology
Tom W. Muir, PhD, Princeton University

5:10 PM

Networking Reception and Poster Session

6:00 PM

Close

Speakers

Organizers

Elizabeth Boon, PhD

Stony Brook University

Elizabeth Boon grew up in Durham, NC. She received her A.B. with Highest Honors in Chemistry from Kenyon College in 1997 and her PhD from the California Institute of Technology in 2003. Liz completed a NIH Postdoctoral Fellowship at the University of California, Berkeley before starting at Stony Brook University in the fall of 2006. She has received several awards for her research including the Presidential Early Career Award for Scientists and Engineers, the American Chemical Society PROGRESS/Dreyfus Lectureship Award, The NYSTAR Watson Young Investigator Award, the Office of Naval Research Young Investigator Award, and the Rising Star Award from the Research Foundation of the State University of New York. In 2011 the Kavli Foundation and the National Academy of Sciences elected Liz a Kavli Fellow. Current research in her lab focuses on determining and characterizing the biochemical pathways responsible for regulating bacterial group behaviors.

Anthony A. Sauve, PhD

Weill Cornell Medical College

Anthony Sauve was born in Los Angeles and grew up in Thousand Oaks, California. He achieved a Bachelor of Arts in Biochemistry from the University of California at Berkeley and was elected Phi Beta Kappa as a Junior. He attended graduate school at Princeton University and earned a PhD in Chemistry, working in the laboratory of John T. Groves, a world expert on the mechanisms of catalytic heteroatom transfer reactions. He was an NIH postdoctoral fellow in the laboratory of Vern L. Schramm, an expert on the uses of isotopes to elucidate catalytic mechanism, and while there began work on the sirtuin enzymes. Dr Sauve described the intricate mechanism of sirtuin deacetylation in 2001, and the mechanism of nicotinamide regulation in 2003. He joined the faculty of Weill Cornell Pharmacology in 2004, and is now Associate Professor of Pharmacology. Dr Sauve’s research interests include the enzymology of sirtuins, the development of chemical tools to study sirtuins in cells and the elucidation of enzyme mechanisms and pathways for NAD biosynthesis in microbial and mammalian cells.

Jennifer S. Henry, PhD

The New York Academy of Sciences

Keynote speaker

Tom W. Muir, PhD

Princeton University

Tom Muir is an expert in protein engineering and its application to studying cellular signaling networks. His lab has developed a suite of chemistry-driven tools for studying the structure and function of proteins in the test tube and in live cells. In addition, his laboratory employs cutting edge methods in protein engineering (computational protein design and directed evolution), structural biology (NMR spectroscopy and x-ray crystallography) and informatics (co-variation analysis). Dr. Muir received his BS in chemistry and his PhD in organic chemistry, both from the University of Edinburgh. After studying bioorganic chemistry as a postdoc and then as a senior research associate at The Scripps Research Institute, he joined The Rockefeller University in 1996 as Assistant Professor. He became the Richard E. Salomon Family Professor in 2005. In 2010 Professor Muir joined Princeton University where he is the Van Zandt Williams Jr. Class of ’65 Professor of Chemistry and Professor of Molecular Biology. Dr. Muir has received many awards, including the Blavatnik Award for Young Scientists, the Irving Sigal Young Investigator Award in 2005 and a Burroughs Wellcome Fund New Investigator Award. Dr. Muir is a fellow of the American Association for the Advancement of Science.

Speakers

Chelsea Higgins

Lai lab, Albert Einstein College of Medicine

Chelsea Higgins received a BA in Electronic Media from the George Washington University in Washington, DC in 2004 before going on to complete a second BA in Chemistry from Western Connecticut State University in 2008. She is currently a PhD candidate at the Albert Einstein College of Medicine in the Lai Lab where she studies mechanisms of class I viral membrane fusion.

Miguel Jimenez

Cornish lab, Columbia University

Miguel Jimenez was born in Bogota, Colombia and later moved to Irvine, California. He received his B.A. in Chemistry in 2011 at Harvard University, where he worked in the laboratory of Stuart Schreiber to expand the scope of ring-closing metathesis. He is currently pursuing his Ph.D. at Columbia University in the laboratory of Virginia Cornish where he is developing technologies for pathway engineering and unnatural amino acid mutagenesis.

Suzanne T. Thomas

Sampson lab, Stony Brook University

Suzanne Thomas earned her Bachelors of Science degree in chemistry in 2006 from Susquehanna University, located in Selinsgrove, Pennsylvania. Subsequently, she joined Stony Brook University to pursue her Ph.D. in chemistry in the laboratory of Nicole S. Sampson. Suzanne’s work is focused on understanding the biochemical function of mycobacterial enzymes involved in cholesterol metabolism.

Stéphane Larochelle, PhD

Fisher lab, Mount Sinai School of Medicine

Stéphane Larochelle grew up in Quebec, Canada, and attended McGill University in Montreal where he obtained both Bachelor of Science and PhD degrees. His graduate work focused on the identification and characterization of new protein kinases genes in Drosophila melanogaster, in the laboratory of Beat Suter, where the focus was the genetics of oogenesis and embryonic development. He subsequently joined the laboratory of Robert Fisher where he continued to study protein kinases as regulators of cell proliferation. Following a short stint with Jean-Marc Egly at the IGBMC in Strasbourg, he returned to New York and the Fisher lab where his ongoing efforts combine classical biochemistry with the new tools of chemical genetics to the study protein kinases involved in regulating the cell cycle and gene expression. Dr. Larochelle was the recipient of a Canadian Cancer Society Terry Fox research fellowship, a Human Science Frontier Project (HSFP) short-term fellowship, and of the 2007 MSKCC research fellow award.

Todd A. Wenderski, PhD

Tan lab, Memorial Sloan–Kettering Cancer Center

Todd Wenderski began chemistry research as a freshman at Colorado School of Mines, studying organometallic coupling reactions with Professor C. Jeff Harlan, and received his Bachelor of Science degree in 2004. Todd then moved to the University of California at Santa Barbara for his PhD, and worked in the laboratory of Thomas R. R. Pettus where he focused on the synthesis of complex natural products. Todd started his postdoc with Derek S. Tan at Memorial Sloan–Kettering Cancer Center in 2010. He is currently developing a general and efficient method for the synthesis of challenging natural product-like scaffolds.

Prachi Anand, PhD

Holford lab, Hunter College, CUNY and The American Museum of Natural History

Prachi was born and grew up in India, received her Masters in 2004 and Doctrate in 2010 in Biomedical Sciences from Delhi University, Delhi, India. During her doctorate she worked towards the therapeutic approaches of Diabetes mellitus, a debilitating disease known since antiquity from natural products. She was successfully able to isolate a few antidiabetic compounds in fairly pure form from medicinal plants and was able to elucidate their antidiabetic mechanism of action by in vitro and in vivo studies. She has also published five articles in peer reviewed journal. As her interest being always in knowing natural resources, she met with Dr. Holford in 2009 during Gordon Research Conference- Natural Products and since then she decided to join her group to explore the more unknown from natural resources. She joined Dr. Holford’s group two years ago in May 2010 and though it was all a new field for her but with Mande’s help she was able to synthesize a few disulfide rich terebrid toxins and using an inventive approach successfully able to map the disulfide pattern. Currently she is also working on a project related to the delivery of neuropeptides using viral nanocapsids.

Sponsors

The Chemical Biology Discussion Group is proudly sponsored by




Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

C-Peptide Inhibition of Ebola Virus
Chelsea Higgins, Albert Einstein College of Medicine

Ebola virus (EBOV) is a highly pathogenic member of the Filoveridae virus family for which there are no approved vaccines or therapeutics. EBOV infection involves host and viral membrane fusion mediated by the glycoproteins GP1 and GP2; disulfide linked dimmers that are organized into trimeric spikes on the viral surface. The current model for the mechanism of EBOV membrane fusion indicates GP2 passes through a pre-fusion extended intermediate during which its N- and C-terminal heptad repeat regions (N- and CHR) are exposed before collapsing into the highly stable post-fusion helical bundle conformation, the formation of which is thought to provide the energy required for fusion. The binding of free C-peptide to the temporarily exposed NHR could prevent the helical bundle formation and therefore inhibit viral infectivity. We have shown in collaboration with the Chandran Group that a designed Ebola C-peptide does in fact inhibit infection, but only when conjugated to an arginine-rich segment that targets the C-peptide to the endosome where membrane fusion is thought to occur. Inhibition could possibly be improved through engineered modifications to the current C-peptide design, including modifications that may impact peptide secondary structure and the endosomal delivery mechanism. As an alternative to the Tat sequence, which exhibits some cytotoxicity, we have conjugated the C-peptide to the possibly less toxic arginine-rich Penetratin sequence, or a cholesterol moiety. To improve the binding energetics between the peptide and the GP2 extended intermediate, we have engineered a covalent i to i+3 linker into the C-peptide. This constraint could force the otherwise unstructured peptide to adopt an a-helical conformation, reducing the loss of entropy upon binding.

Coauthors: Jayne Koellhoffer, Emily Miller, Kartik Chandran, and Jon Lai, Albert Einstein College of Medicine

 

Reiterative Recombination for Pathway Engineering: From Yeast to Stem Cells
Miguel Jimenez, Columbia University

Studying and directing the complex and dynamic biology of human embryonic stem cells (hESC) requires working at the multi-gene level. However there is a fundamental gap between methods for manipulating single genes and the complex transcriptional network of hESCs that is exacerbated by the difficulty of culturing hESCs. The next generation of tools for manipulating hESCs must work at the multi-gene level in an efficient and technically robust manner. Our lab has developed a system of in vivo Reiterative Recombination that harnesses the power of homing endonuclease-stimulated homologous recombination for assembling multi-gene pathways in yeast. The methodology consists of a pair-wise system of recycling selectable markers and endonuclease recognition sites that allow indefinite assembly of DNA in vivo. This strategy obviates the need to extract and retransform increasingly larger DNA fragments. Due to its efficiency and technical simplicity we are able to construct not only single pathways but also large libraries of >104 variants enabling the optimization of metabolic pathways. We envision the expansion of such high throughput genetic tools beyond S. cerevisiae, for example in the engineering of human stem cells differentiation.

Coauthors: Zen Liu, Nili Ostrov, Dario Sirabella, Gordana Vunjak-Novakovic and Virginia Cornish, Columbia University

 

Metabolic and Enzymatic Characterization of the Intracellular Growth Operon in Mycobacterium tuberculosis
Suzanne T. Thomas, Stony Brook University

 
New drugs with novel mechanisms of action are required to meet the severe threat to human health posed by the emergence of multidrug and extensively drug resistant strains of Mycobacterium tuberculosis (M. tb). The ability of M. tb to metabolize cholesterol is critical for the maintenance of the M. tb infection. The intracellular growth (igr) operon is required for in vitro growth using cholesterol as a sole carbon source, however, the function of these genes and their role in cholesterol metabolism is yet to be established. Here we describe the biosynthetic preparation of isotopically labeled 13C- [1,7,15,22,26]-cholesterol and employ it as a tool to investigate the cholesterol-derived metabolite profile of the M. tb H37Rv Δigr mutant strain by high resolution LCMS. Culture supernatants from the Δigr mutant accumulate a cholesterol-derived metabolite not observed in H37Rv wild-type or complemented strains. Multidimensional NMR and mass spectral analysis revealed the structure of this cholesterol-derived catabolite to be a late stage metabolic product: methyl 1β-(2'-propanoate)-3aa-H-4α(3'-propanoic acid)-7aβ-methylhexahydro-5-indanone. The computationally annotated functions of the six genes of the igr operon are a lipid transfer protein (ltp2/Rv3540c), two MaoC-like hydratases (Rv3541c and Rv3542c), two acyl-CoA dehydrogenases (fadE29/Rv3543c and fadE28/Rv3544c), and a cytochrome P450 (cyp125/Rv3545c). Heterologous expression in E. coli and biophysical characterization demonstrated that FadE28 forms a heteromeric complex with FadE29, and that likewise, Rv3542c forms a heteromeric complex with Rv3541c; each complex exhibits a novel α2β2 quaternary architecture. Using synthetic substrates analogous to the metabolite identified in M. tb H37Rv Δigr mutant strain, we verified the catalytic activity of the purified, recombinant FadE28-FadE29 and Rv3541c-Rv3542c protein complexes to be dehydrogenation and hydration of the 2'-propanoate-CoA side chain. We conclude the igr operon is required for degradation of the 2'-propanoate side-chain fragment during metabolism of cholesterol by M. tb.

Coauthors: Brian C. VanderVen, Cornell University, David G. Russell, Cornell University, Nicole S. Sampson, Stony Brook University

Chemical Genetics uncovers Cyclin-Dependent Kinase Control of the Initiation-to-Elongation switch of RNA Polymerase II in Human Cells
Stéphane Larochelle, PhD, Mount Sinai School of Medicine

Kinase inhibitors are widely used to infer specific functions of individual protein kinases in vivo. However, because of active-site conservation within the kinase family, these drugs typically display a high degree of target promiscuity in vivo. Although this propensity for multiple-kinase inhibition might be beneficial in some therapeutic contexts, it is undesirable when off-target effects cause toxicity, or when the goal is to elucidate functions of a single kinase. The chemical genetic approach, whereby a mutation within the active site renders a kinase uniquely sensitive to a designed inhibitor, allows for otherwise unachievable selectivity in vivo, while maintaining structural integrity of protein complexes that contain the targeted kinase. By this strategy we uncovered a cyclin-dependent kinase (CDK) cascade essential for promoter-proximal pausing by RNA polymerase II, which is both a gene-specific regulatory strategy and an RNA quality control mechanism. The conserved DRB-sensitivity inducing factor (DSIF) is required to impose the pause, and structural considerations suggested that eviction of transcription initiation factor TFIIE would be necessary for DSIF engagement. The activity of Cdk9 (P-TEFb) is needed to overcome pausing. We show that inhibition of Cdk7—part of TFIIH—increases TFIIE retention and prevents DSIF recruitment at transcribed genes in human cells, leading to attenuated pausing. Cdk7 activates Cdk9 in vitro, and Cdk7 inhibition prevents Cdk9-activating phosphorylation in vivo. Cdk7 thus acts through TFIIE and DSIF to establish, and through Cdk9 to relieve, a kinetic barrier to elongation: incoherent feed forward that could create a window to recruit RNA-processing machinery.

Coauthors: Ramon Amat, PhD1, Kira Glover-Cutter, PhD2, Miriam Sansó, PhD1, Chao Zhang, PhD3, Kevan M. Shokat, PhD3, David L. Bentley, PhD2, and Robert P. Fisher, MD, PhD1
1Dept. of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY
2University of Colorado School of Medicine, Aurora, CO
3Howard Hughes Medical Institute and University of California San Francisco, CA

 

Biomimetic Diversity-Oriented Synthesis of Benzannulated Medium Rings by Oxidative Dearomatization/Ring-Expanding Rearomatization
Todd A. Wenderski, Memorial Sloan–Kettering Cancer Center

Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, due to the limitations of conventional cyclization-based approaches to medium ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts. To address this problem, we have developed an alternative, biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries. Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products. The ring expansion reaction can be induced using one of three complimentary reagents and is energetically driven by rearomatization to a phenol ring adjacent to the scissile bond.

Coauthors: Renato A. Bauer and Derek S. Tan, Memorial Sloan–Kettering Cancer Center, New York, NY 10065

 

Terebrids Can Do it Too: Discovery and Characterization of a Novel Peptide Neurotoxin Tv1 from Venomous Marine Snail Terebra variegata Active on Nicotinic Receptors
Prachi Anand, PhD, Hunter College, CUNY and The American Museum of Natural History

The Conoidea superfamily comprised of cone snails, terebrids, and turrids, produce disulfide rich peptides to subdue their prey and are an exceptionally promising group for discovering therapeutically relevant natural peptide neurotoxins. For the past 30 years, efforts to characterize venomous snail peptides has focused on cone snail peptide toxins, conopeptides, leading to the successful distribution of the first cone snail drug, ziconotide (Prialt), an analgesic. In contrast to cone snails, very little is known of terebrid peptides, teretoxins. Described here is the discovery, and structural and functional characterization of a novel terebrid neurotoxin, Tv1, from Terebra variegata. Tv1 was identified using a charge-enhanced ETD chemical derivatization strategy in combination with de novo sequencing. Based on the classification of conotoxin superfamilies, Tv1, which is 21 amino acids long with six cysteines (CC-C-C-CC), belongs to mini MIII superfamily, for which there are no reported disulfide scaffolds. To characterize the disulfide connectivity of Tv1 an inventive partial reduction and dual alkylation technique was used to label the cysteine pairs followed by LC-MS/MS analysis. , Tv1's predicted disulfide scaffold is Cys1-Cys5, Cys2-Cys6 and Cys3-Cys4. The cysteine scaffold was determined using MassHunter Bioconfirm B.05 software, and further confirmed by NMR studies. Similar to other M superfamily ψ conotoxins, preliminary results indicate Tv1 significantly blocks Nicotinic Acetylcholine receptors, specifically α6β2β3 subtype in micromolar concentrations. The α6 subunit has gained increasing attention due to its putative role in nicotine reinforcement and addiction and its selective down-regulation in Parkinson's disease. Further biological assays are in progress to confirm the biological activity of Tv1. This is the first structural and biological characterization of a teretoxin peptide.

Coauthors: Alexander Grigoryan1, Vadi Bhat, PhD2, Beatrix Ueberheide, PhD3, Alexandre Kouriatov4, Brian Chait, PhD5, Jon Lindstrom, PhD4, Sebastian Poget, PhD6 and Mandë Holford, PhD
1Hunter College, CUNY and The American Museum of Natural History
2Agilent Technologies
3New York University-Medical Center
4The University of Pennsylvania
5The Rockefeller University
6College of SI, CUNY

 

Chromatin: An Expansive Canvas for Chemical Biology
Tom W. Muir, PhD, Princeton University

Understanding protein function is at the heart of experimental biology. Perhaps one of the grandest contemporary challenges in this area is to catalogue and then functionally characterize protein posttranslational modifications (PTMs). Modern analytical techniques reveal that most, if not all, proteins are modified at some point; it is nature's way of imposing functional diversity on a polypeptide chain. Understanding the structural and functional consequences of all these PTMs is a devilishly hard problem. While standard molecular biology methods are of limited utility in this regard, modern protein chemistry has provided powerful methods that allow the detailed interrogation of protein PTMs. In this lecture I will discuss several protein ligation technologies developed for preparing modified proteins, and will highlight these methods through specific applications to chromatin biology.

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