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.

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.

Image Credits

• 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)