Studies of protein molecular movement reveal previously unseen binding sites

Some of the toughest challenges in treating disease come from "can't take" proteins whose structure and role in disease are known but seemingly unable to be targeted by drugs that bind to them
.
Researchers at KAUST have now demonstrated that the molecular movement of many "drug-resistant" proteins can actually expose sites where drugs can bind
.

The study focused on a specific molecular region known as the BTB domain, which is known to be a key part of
more than 350 proteins.
It binds proteins to other proteins, influencing complex genetic and molecular signaling processes
that are essential for many cellular activities.

More than 80 known BTB-containing proteins are transcription factors that control gene activity, meaning many of them are linked
to cancer.
Because BTB domains have proven difficult to target by drugs, these cancers
are often fatal.

The KAUST team, together with colleagues from the University of Michigan, USA, performed a detailed analysis
of the molecular movement of the BTB domain in 3 proteins associated with cancer.

The results reveal the role of
molecular motility in influencing the ability of small molecules (collectively known as ligands) to bind to the BTB domain.
This reveals concealed binding sites – unlike static structures, dynamic regions of the BTB domain appear to bind
to ligands.

Jaremko from the KAUST team said: "This means that some target proteins that do not seem to be able to be taken can now be reconsidered, with a firm desire to find new lead compounds
for cancer drug development.
" "The protagonist of our study, known as the MIZ1 protein, is involved in the oncogene c-MYC of more than 70% of cancers and can now be targeted
for drug discovery activities.
"

The researchers were surprised to find that the movement of proteins is so important in controlling ligand binding sites, while acknowledging that in retrospect it seems logical
.

Lead author Vladlena Kharchenko is a former doctoral student at KAUST and is now a postdoctoral
fellow at the Albert Einstein College of Medicine in the United States.
The next challenge, she says, is to fully understand the mechanisms
that make molecular movement make hidden binding sites so difficult to detect and interact.

Kharchenko concluded: "We also want to find these sites in other proteins to advance the drug discovery process for many other proteins that are currently incurable, and ultimately bring new hope
for the treatment of currently incurable diseases, including many forms of cancer.
"