Structure of DNA repair complex reveals workings of powerful cell motor

Over the last years, two teams of researchers at The Scripps Research Institute have steadily built a model of how a powerful DNA repair complex works. Now, their latest discovery provides revolutionary insights into the way the molecular motor inside the complex functions – findings they say may have implications for treatment of disorders ranging from cancer to cystic fibrosis.

In a paper published in an Advance Online Edition of Nature Structural and Molecular Biology March 27, 2011, the scientists say that the complex's motor molecule, known as Rad50, is a surprisingly flexible protein that can change shape and even rotate depending on the task at hand.

The finding solves the long-standing mystery of how a single protein complex known as MRN (Mre11-Rad50-Nbs1) can repair DNA in a number of different, and tricky, ways that seem impossible for "standard issue" proteins to do, say team leaders Scripps Research Professor John Tainer, Ph.D., and Scripps Research Professor Paul Russell, Ph.D., who also collaborated with members of the Lawrence Berkeley National Laboratory on the study.

They say the finding also provides a critical insight into the ABC-ATPase superfamily of molecular motors, of which Rad50 is a member.

"Rad50 and its brethren proteins in this superfamily are biology's general motors," said Tainer, "and if we know how they work, we might be able to control biological outcomes when we need to."

For example, knowing that Rad50 changes its contour to perform a function suggests it might be possible to therapeutically target unique elements in that specific conformation. "There could be a new generation of drugs that are designed not against an active site, like most drugs now (an approach that can cause side effects, but against the shape the protein needs to be in to work," Tainer said.