Some of the most difficult challenges in treating disease are presented by “non-curable” proteins whose structures and roles in disease are known but seemingly unable to be targeted by drugs that bind to them. Researchers at KAUST have now shown that the molecular motion of many “unmovable” proteins can, in fact, reveal sites where drugs could bind.
The research focuses on a particular molecular region called the BTB domain, which is known to be a critical component of more than 350 proteins. It enables proteins to bind to other proteins to influence complex genetic and molecular signaling processes central to the activities of many cells.
More than 80 known BTB-containing proteins are transcription factors that control the activities of genes, a role that means many of them are involved in cancer. Because the BTB domain is difficult to target with drugs, these cancers are often fatal.
KAUST’s team, together with colleagues from the University of Michigan in the US, performed a detailed analysis of the molecular movements of BTB domains in three proteins involved in cancer.
The results revealed the role of molecular motion in influencing the ability of small molecules, collectively known as ligands, to bind to the BTB domain. This revealed cryptic binding sites – dynamic regions of BTB domains that seem available to bind to ligands, unlike the static structures.
“This means that some apparently non-drug target proteins can now be reconsidered, with the firm hope of identifying new lead compounds for cancer drug development,” says Łukasz Jaremko from the KAUST team. “The hero of our study, called the MIZ1 protein, has been linked to c-MYC, the oncogenic cancer-causing gene of more than 70 percent of cancers, and can now be used in drug discovery campaigns.”
The researchers were surprised to discover how important the movement of proteins may be in controlling ligand binding sites, while acknowledging that it makes sense in hindsight.
First author Vladlena Kharchenko, a former KAUST Ph.D. student and now a postdoctoral fellow at Albert Einstein College of Medicine in the US, says the next challenge is to fully understand the mechanisms that allow molecular motions to make cryptic binding sites so difficult to detect and interact with.
“We want to find these sites in other proteins as well, to advance the process of drug discovery for many other proteins that are currently untreatable and ultimately give new hope for the treatment of currently incurable diseases, including many cancers,” concludes. Kharchenko.
Increased slow dynamics defines ligandability of BTB domains
Article publication date
Nov 16, 2022
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