A KAUST-led team of researchers has revealed properties of the MIZ1 protein (illustrated above). Their findings could advance drug discovery for previously incurable diseases, including some forms of cancer. Credit: © 2022 KAUST
Many pharmaceutical drugs function through the binding of small molecules to target proteins, which requires a suitable site on the protein for drug molecules to attach. Numerous diseases, including cancers, involve proteins that are considered “undruggable” due to the lack of apparent binding sites that can be targeted with small molecules. New research conducted by King Abdullah University of Science & Technology (KAUST) researchers, along with colleagues from the University of Michigan, reveals that some “undruggable” proteins have “cryptic” binding sites, and that the molecular motions of certain proteins can affect their ligandability.
The researchers focused their study on the BTB domains of three cancer-involved proteins – LFR, KAISO and MIZ1. More than 80 known BTB-containing proteins are transcription factors that control the activities of genes, a role that means many of them are implicated in cancer, but the BTB domain has long been difficult to target with drugs. The team performed fragment screening using protein-observed solution nuclear magnetic resonance (NMR) spectroscopy, screening each of the three proteins against a library of 600 small molecules. The BTB domain of one of the proteins, MIZ1, was found to bind to multiple molecules, while LFR and KAISO were not found to bind to any ligands despite their structural similarity to MIZ1.
To understand the factors affecting the ligandability of the BTB domain of MIZ1 compared with those of LFR and KAISO, the team further investigated the molecular dynamics of each protein using solution NMR spectroscopy. This revealed that MIZ1 had a distinct dynamics profile from the other two proteins, which better enables it to bind to small molecules when changing between “closed” and “open” conformations. While the closed version does not allow for small molecule binding, the open version contains hidden binding sites that may not be identified when looking at the static structure of the protein’s BTB domain. This research provides insights into how researchers could identify more cryptic binding sites using solution NMR to study the dynamic motions of different proteins. This study was published in Nature Communications.
“This means that some seemingly undruggable target proteins can now be reconsidered, with the firm hope of identifying novel lead compounds for anticancer drug development,” said co-corresponding author Łukasz Jaremko. “The hero of our study, called the MIZ1 protein, is linked to c-MYC, the oncogene cancer-causing gene of over 70 percent of cancers, and can now be targeted for drug discovery campaigns.
The next challenge for the researchers will be to fully understand the mechanisms that allow molecular movements to make cryptic binding sites so hard to detect and interact with, said first author Vladlena Kharchenko.