Science + Platform
Intrinsically Disordered Proteins
Hundreds of thousands of proteins fill our cells and perform essential tasks inside our bodies, from providing structural support to passing signals, catalyzing reactions, and reading DNA.
If a protein undergoes a mutation or is misregulated, that protein can malfunction, which can cause disease. Drugs are commonly designed to stop or prevent such a protein from malfunctioning. For example, a drug may correct a protein’s function or degrade all copies of a protein that carry a particular mutation.
A structure-based approach is often followed to design drugs that regulate a particular protein. Specifically, scientists determine that protein’s 3D structure and use information about its shape and the positions of its atoms to design a drug that binds tightly and specifically to that protein in a way that restores normal cell function. The resulting drug candidates are then tested extensively before entering clinical trials. The first drugs developed using structure-based methods were for HIV and influenza in the 1990s. Since the early 2000s, structure-based approaches were used to discover over half of all new small molecule drugs.
However, 30% of proteins are predicted to not have a single 3D structure. Instead, they have evolved to fluctuate between an ensemble of short-lived conformations, which enable them to perform essential functions in cells. Many proteins implicated in cancers and neurodegenerative disorders, as well as many bacterial and viral proteins, belong to this class of shapeshifting proteins, termed intrinsically disordered proteins (IDPs). For these proteins, obtaining detailed structural information that could guide structure-based drug discovery is challenging, and no drugs exist that target these proteins.
Prototypical Intrinsically Disordered Protein Targets
Tumor suppressor with mutations
in over half of tumors
Normally disordered, but forms aggregates like those shown here in the brains of Alzheimer’s patients
Bacterial antitoxin protein that releases a toxin to trigger cell death
The challenge in determining detailed structural information for the short-lived conformations adopted by IDPs lies in the way protein structures are determined. Current experiments detect the average conformation of a protein over time and across its population. If a protein maintains relatively the same shape over time, the observed average structure will be meaningful and can be used to guide drug discovery. However, if a protein changes shape rapidly over time, as IDPs do, then the observed average structure will be meaningless.
IDPs also challenge current computational methods. Existing technologies, developed to describe compact and stable proteins, have not been able to consistently capture the extended conformations adopted by IDPs or the timescales at which they fluctuate.
New Equilibrium combines big data, artificial intelligence, and biophysical experiments to freeze-frame IDPs, allowing us to accurately visualize the ensemble of different conformations that an IDP adopts. This 3D structural information enables us to design and optimize drugs targeting IDPs using structure-based drug design methods.
Our goal is to specifically drug malfunctioning IDPs and restore normal cellular function. First, we utilize bioinformatics and mutagenesis assays to identify the functional roles of individual IDP states. Next, we compare the set of conformations adopted by a “wild-type” protein in healthy cells and those from an impaired form of the protein in diseased cells. By solely targeting pathogenic conformations in diseased cells, the healthy protein remains unimpaired, presenting a new route to low-toxicity drugs.
Our platform depends on cross-disciplinary insights from physics, chemistry, mathematics, computer science, biophysics, and cell biology. Across our development, we are focused on thinking about how things should be done, instead of how they have been done.
Relevant Publications from our Team
- Nguyen, H., Ábrányi-Balogh, P., Petri, L., Mészáros, A., Pauwels, K., Vandenbussche, G., Keserű, G., Tompa, P. (2020) Targeting an Intrinsically Disordered Protein by Covalent Modification. In: Kragelund B., Skriver K. (eds) Intrinsically Disordered Proteins. Methods in Molecular Biology, vol 2141. Humana, New York, NY.
- Burger, V., Vandervelde, A., Hendrix, J., Konijnenberg, A., Sobott, F., Loris, R. Stultz, C.M. (2017) Hidden states within disordered regions of the CcdA antitoxin protein. Journal of the American Chemical Society 139 (7), 2693-2701.
- Ziegler, Z., Schmidt, M., Gurry, T., Burger, V., Stultz, C. (2016) Mollack: a web server for the automated creation of conformational ensembles for intrinsically disordered proteins. Bioinformatics.
- Cedeño C., Raveh-Hamit H., Dinnyés A., Tompa P. (2015) Towards Understanding Protein Disorder In-Cell. In: Felli I., Pierattelli R. (eds) Intrinsically Disordered Proteins Studied by NMR Spectroscopy. Advances in Experimental Medicine and Biology, vol 870. Springer, Cham.
- Guharoy, M., Pauwels, K. and Tompa, P. (2015) Intrinsic structural disorder. Cell 161: 1230–1230.e1.
- Tompa, P. (2014) Multisteric regulation by structural disorder in modular signaling proteins: an extension of the concept of allostery. Chem. Rev. 114, 6715–6732.
- Burger, V., Gurry, T., Stultz, C. (2014) Intrinsically disordered proteins: where computation meets experiment. Polymers 6(10), 2684-2719.
- Tantos, A., Szabo, B., Lang, A., Varga, Z., Tsylonok, M., Bokor, M., Verebelyi, T., Kamasa, P., Tompa, K., Perczel, A., Buday, L., Lee, S., Choo, Y., Han, K.-H., Tompa, P. (2013) Multiple fuzzy interactions in the moonlighting function of thymosin-β4. Intrinsically Disordered Proteins, 1:1, e26204.
- Burger, V.*, Ramanathan, A.*, Savol, A., Stanley, C., Agarwal, P., Chennubhotla, C. (2012) Quasi-anharmonic analysis reveals intermediate states in the Nuclear Co-Activator Receptor Binding Domain ensemble. Pacific Symposium on Biocomputing 17, 70-81.
- Tompa, P. (2009) Structure and Function of Intrinsically Disordered Proteins. CRC Press, a Taylor and Francis group, Inc., New York, San Francisco
- Tompa, P. (2002) Intrinsically unstructured proteins. Trends Biochem. Sci. 27 (10), 527-533.
Drug Discovery for IDPs in the News
- Branchi, Vanessa. The Top 10 Emerging Technologies of 2019. Scientific American. July 1, 2019.
- Dance, Amber. Drugging the Disorderome Strategies for targeting intrinsically disordered proteins. The Scientist. September 30, 2017.
- E.Coli cell illustration by David S. Goodsell, The Scripps Research Institute. doi: 10.2210/rcsb_pdb/goodsell-gallery-001
- Structure-based drug discovery illustration uses PDB ID 1OHR (Kaldor, et al. J. Med. Chem. 1997)