This Year’s Topic
We’re so very thrilled to be exploring the research from Celia Schiffer, who was recently honored with the William C. Rose Award. Dr. Schiffer has founded both the Schiffer Lab and the Institute for Drug Resistance, which both study drug resistance. We’re excited about the opportunity to work with Dr. Schiffer’s lab for a number of reasons:
- Her research takes on a multidisciplinary approach, using principles of organic synthesis, structure-based drug design, crystallography, thermodynamics and enzyme kinetics, virology, co-evolution, and much more – all both fascinating and critical in college and career!
- The Schiffer lab studies many diseases, including HIV, Hepatitis C, and Influenza, among others. They study a LOT of different proteins, from HIV-1 protease, to Influenza hemagglutinin, to Dengue NS2B/NS3 protease.
- Dr. Schiffer has LOTS of structures in the PDB from which to choose!!!
- All of her publications (over one hundred!) are accessible from her website.
Exploring the Ribosome
Check out this video (are we doing a video like this this year???)
Learning about the Schiffer Lab
Watch the short video below to see Dr. Schiffer explain what her lab studies, and how they are working to counter drug resistance
And, learn more about the lab and the work they do from one of her Doctoral students, Ashley Matthew!
Suggested Approach
Start exploring background information to narrow your research focus!
Background Reading
You might want to start by exploring (comparing) information about translation from various textbooks (intro bio, genetics, cell biology, biochemistry).
Also, listed below are the citations for articles from the Schiffer Lab that will be a good starting place. Those with the full text online have the link to the full text; otherwise, your institution may have access to some of the Journals they are hosted in.
- (Henes et al., 2019; Leidner et al., 2018, 2019; Lockbaum et al., 2019; Matthew et al., 2018; Prachanronarong et al., 2016; Rusere et al., 2018)
- Henes, M., Lockbaum, G.J., Kosovrasti, K., Leidner, F., Nachum, G.S., Nalivaika, E.A., Lee, S.-K., Spielvogel, E., Zhou, S., Swanstrom, R., et al. (2019). Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance. ACS Chem. Biol.
- Leidner, F., Kurt Yilmaz, N., Paulsen, J., Muller, Y.A., and Schiffer, C.A. (2018). Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease. J. Chem. Theory Comput. 14, 2784–2796. Full text here
- Leidner, F., Kurt Yilmaz, N., and Schiffer, C.A. (2019). Target-Specific Prediction of Ligand Affinity with Structure-Based Interaction Fingerprints. J. Chem. Inf. Model.
- Lockbaum, G.J., Leidner, F., Rusere, L.N., Henes, M., Kosovrasti, K., Nachum, G.S., Nalivaika, E.A., Ali, A., Kurt Yilmaz, N., and Schiffer, C.A. (2019). Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease. ACS Infect. Dis. 5, 316–325.
- Matthew, A.N., Leidner, F., Newton, A., Petropoulos, C.J., Huang, W., Ali, A., KurtYilmaz, N., and Schiffer, C.A. (2018). Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3/4A Protease. Structure 26, 1360-1372.e5.
- Prachanronarong, K.L., Özen, A., Thayer, K.M., Yilmaz, L.S., Zeldovich, K.B., Bolon, D.N., Kowalik, T.F., Jensen, J.D., Finberg, R.W., Wang, J.P., et al. (2016). Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase. J. Chem. Theory Comput. 12, 6098–6108.
- Rusere, L.N., Matthew, A.N., Lockbaum, G.J., Jahangir, M., Newton, A., Petropoulos, C.J., Huang, W., Kurt Yilmaz, N., Schiffer, C.A., and Ali, A. (2018). Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants. ACS Med. Chem. Lett. 9, 691–696. Full text here
It might be an interesting discussion to compare the depth of the “facts” in the textbook with those in current research articles!
Another discussion might involve comparing prokaryotic and eukaryotic processes – and why/whether it is of value to study prokaryotic systems
- Another discussion might involve comparing prokaryotic and eukaryotic processes – and why/whether it is of value to study prokaryotic systems
- With this background information, you should be ready to tackle some of the Dunham lab articles. Some of the articles list the associated pdb files, either on the first or last page or in the figure legends. If you can’t find the pdb files listed in the article, search the Protein Databank for the first author. Structures are listed in order of deposit, with the most recent at the top. Look for the primary citation that matches your paper to find associated pdb files. Pick a topic that intrigues you and start exploring.
- If you want to explore the stringent response (bacteria under stress), here’s a good review from Trends in Microbiology
For those of you who have worked with Jmol in the past, there will be a few twists and turns in this year’s project. If your team chooses to work with a model of the ribosome, there will be a few extra steps in handling the large data files for such a large structure. It’s an opportunity to expand your horizons and pick up a few more tools in your molecular visualization toolkit. Once you have narrowed down which PDB file you want to use, the molecular story you want to tell, and what you want to include in your model, please contact Margaret (franzen@msoe.edu) to set up a Zoom meeting with your team to discuss your model design.