Category: Allen, Karen
Professor Whitty was awarded a 4 Year grant by the National Institute of Health (NIH) to further his studies of NF-kB Modulators. The title of the Research Project is: Structure and Mechanism of NF-kB Essential Modulator (NEMO).
This funding will allow Professor Whitty and his Co-PIs Professors Karen Allen of Chemistry and Thomas Gilmore of Biology to advance our understanding of the signaling scaffold protein NF-κB essential modulator (NEMO), a component of the inhibitor of κB kinase (IKK) complex, which is a key regulatory node for NF-κB signaling. In addition to NEMO playing a role in the chronic hyperactivity of NF-κB in human diseases, mutations in NEMO are found in several human immunodeficiency diseases. The long-term goals of the project are to understand how scaffolding proteins such as NEMO use conformational change to regulate the functional interactions between the signaling proteins that are bound to them, to elucidate the structural basis for disease-causing mutations in key regions of NEMO, and to identify new target sites for small molecule drugs that modulate NEMO activity.
Congratulations to Professors Whitty, Allen and Gilmore and their research team!
Continuing their highly productive (32 publications), 20-year collaboration, Professor Karen Allen and Dr. Debra Dunaway-Mariano, University of New Mexico, have received a 4-year, $1.26 million award from the NIH. The team is known for much of the current understanding of catalysis and specificity of the Haloalkanoic Acid Dehalogenase Superfamily (HADSF). This current award, “Structure and Function of HAD Phosphatase Partners Dullard and Lipin,” represents a new and highly innovative research direction for the the Co-Investigators. Using an interdisciplinary approach, they will investigate the structural basis for the function of two enzymes that utilize the same protein scaffold to interact with and dephosphorylate macromolecules and phospholipids at the cell membrane. The Co-Principal Investigators bring their respective expertise to address the problem. Karen Allen will direct the protein chemistry, bioinformatics, X-ray crystallographic and Small-angle X-ray Scattering aspects of this project. Debra Dunaway-Mariano will direct the substrate screening, assay development, and radio-labeled vesicle binding studies.
By defining the structural features of enzymes that allow recognition of specific proteins and cell membrane components, the study will provide significant insight into the complexities of cell lipid metabolism. The findings will lay the foundation for the rational design of therapeutic agents to treat the diseases associated with diabetes and clinically identified defects in fat metabolism.
Professor Karen Allen and Dr. Jeff Bacon, staff crystallographer of the Chemical Instrumentation Center (CIC), demonstrated the power of X-ray crystallography to local area high school students as part of an American Crystallographic Association (ACA) outreach program. The scientists hosted two groups. In March, 12 students from Acton-Boxborough Regional High School and their teacher, Aaron Mathieu visited; and in May, 15 students from Prospect Hill Academy and their teacher, Katie Boiteau visited. Both groups had grown their own crystals of lysozyme, prepared in their school laboratory or at CityLab, a fully equipped biotechnology laboratory in the BU School of Medicine that is available to Middle and High School students, educators, and other groups.
Each group learned about the history and theory of X-ray crystallography in the determination of protein structure from Professor Karen Allen, one of the world’s leading crystallographers. After a one-hour classroom discussion, the students brought their crystal samples to the CIC’s X-ray laboratory for a practical demonstration of the experiment with Dr. Bacon. The students examined their crystals under a microscope, and one crystal from each group was mounted on the instrument for a unit cell determination.
Interested students have been invited to the ACA’s annual meeting, to be held in Boston at the end of July, where they will have the opportunity to present a poster and to learn more about structural biology. The program is an outreach activity of the ACA Young Scientists’ Special Interest Group, and was supported by a donation of crystallization supplies from Hampton Research.
Additional photos can be seen on the BU Chemistry Flickr site.
Professor Karen Allen, an Associate Editor of Biochemistry, has contributed to the fifth episode of the American Chemical Society’s series, ‘Publishing Your Research 101.” The episode addresses “Ethical Considerations for Authors and Reviewers.” This series interviews experts such as Professor Allen to obtain their insights on practical, real world questions and issues facing authors of research papers. Further information about this episode and the entire series can be found on the ACS Website.
Learning about the ins and outs of scholarly publishing is an important aspect of training as a scientist. For its September 2011 ACS on Campus event, “Basics of Peer-Review and Scholarly Publishing: From the Editors Themselves,” the American Chemical Society has invited Professor Karen Allen to speak on the topic of how to begin the manuscript writing process and how to prepare a manuscript for submission and review.
ACS on Campus takes place from September 29th – 30th at Harvard University and at the Massachusetts Institute of Technology (MIT). See the ACS Website for more information.
The Boston University Department of Chemistry has received funds from the NSF MRI program to acquire a Circular Dichroism (CD) Spectrometer, which will enhance the research of scientists in several departments encompassing biological and organic chemistry.
In addition to the Principal Investigator, Professor Karen Allen, there are five major users at BU whose research will benefit from this instrument and more than ten other scientists whose research capabilities will be significantly advanced.
The new CD spectrophotometer will be housed in the Chemistry Instrumentation Center (CIC) located in the Boston University Chemistry Department and headed by Dr. Norman Lee, who will manage the acquisition and integration of the new instrument. Dr. Jeffrey Bacon will oversee the instrument’s maintenance, user training, and data collection.
The results of the research that use the CD will be disseminated broadly to enhance scientific and technology understanding. At the same time that it advances discovery and understanding, the new CD will promote training in the analytical training of physical properties of organic and inorganic molecules at both the graduate and undergraduate levels in Chemistry and Biology Departments and in the Biochemistry and Molecular Biology program.
A recent publication in the Journal of the American Chemical Society by Professor Allen and her Research Group, “Engineering Encodable Lanthanide-Binding Tags into Loop Regions of Proteins,” was evaluated in by Professor Gottfried Otting in Faculty of 1000.
It is Professor Otting’s view that, “this paper shows for the first time that a lanthanide-binding peptide can be inserted into the turn connecting two strands of a beta-sheet without affecting the structure and activity of the protein.”
The Burroughs Wellcome Fund (BWF) uses Collaborative Research Travel Grants to facilitate biomedical research among laboratories in the US and abroad. This February, two Chemistry groups received these competitive awards.
One of the grants will support Professor Pinghua Liu and his graduate student, Jinzhao Shen, to go to Beijing to work in the laboratory of Professor Xiaoping Chen of the Chinese Academy of Sciences. They will collaborate with Professor Chen’s group to develop new anti-microbial drugs, focusing initially on new anti-malaria drugs for multi-drug resistant strains. Specifically, they will build marine natural product libraries and screen them for anti-malaria activities.
The second grant will support graduate student, Daniel Saltzberg, in the Allen Group. Mr. Saltzberg will work with Dr. Hiro Tsuruta’s group at the Stanford Synchrotron Radiation Lightsource to probe the specific interactions governing ligand binding in a large superfamily of metabolic enzymes. These studies will provide insight into the evolution of functional diversity in this superfamily.
Professor of Chemistry Karen Allen and Associate Professor of Chemistry Adrian Whitty gave a “Discoveries” talk to BU Alumni on December 1, 2010. Sponsored by the BU Alumni Association and the College of Arts & Sciences, the Discoveries lecture series taps the strength of BU faculty to give alumni a deeper look into the world and their lives.
The seminar, Lessons to be Learned from Cells: From Molecular Basis to Disease, highlighted advances and obstacles in current drug discovery and described how work at Boston University on NEMO, a protein in the pathways involved in human inflammatory diseases and cancers, aims to address critical problems.
There are many medically important drug targets that current drug discovery technology is not able to address. Collaborative basic research in Chemistry, Biology, and Biochemistry is key to solving these intractable problems to enable the discovery of new classes of drugs. A multidisciplinary team at Boston University, led by Associate Professor of Chemistry Adrian Whitty, aims to develop new approaches for challenging molecular targets. The National Institute of General Medical Sciences awarded this team a 4-year, $1.6 million grant entitled Design of Macrocyclic Inhibitors of the NEMO/IKKα/β Protein-Protein Interaction.
Only about 10% of the potential drug targets in the human genome have been successfully targeted with marketed drugs. Of the remaining 90%, many are intracellular proteins whose function is critically dependent on their reversible interactions with other proteins. Despite decades of effort by the pharmaceutical industry, developing oral drugs that inhibit protein-protein interactions (PPIs) has rarely succeeded and has become recognized as a major scientific and technological challenge.
The primary goal of this project is to determine whether the use of a class of natural product-inspired compounds called macrocycles constitutes a broadly applicable method for developing oral drugs against PPI targets. As a first challenge, the team is attempting to develop macrocycles that block the activity of NEMO, a key component of the IKK complex that activates NF-κB signaling. Chronic hyperactivity of the NF-κB pathway is associated with many human inflammatory diseases and cancers. Thus, the development of drug-like inhibitors of this pathway is highly relevant to public health.
The work will determine whether appropriately designed synthetic macrocycles can inhibit PPI targets while maintaining good drug-like properties. In terms of NF-κB and disease, their work will provide a means for testing whether inhibiting the interaction of NEMO with IKK—as a more targeted alternative to completely ablating all IKK activity—represents a useful new approach for attenuating inflammation.
In addition to Professor Whitty (quantitative biochemistry and drug discovery), the multidisciplinary research team comprises Professors Sandor Vajda and Dima Kozakov (computational chemistry), John Porco and Aaron Beeler (macrocycle synthesis), Karen Allen (X-ray crystallography), and Tom Gilmore (NF-κB pathway biology).