Study results challenge conventional theory of drug design.

Scientists from The Scripps Research Institute have uncovered evidence that ligand dynamics affect cell signaling. They believe that their findings challenge the current theory about how ligands bind to proteins and how such drugs are designed.

The study was published October 10 in an advance, online edition of Nature Chemical Biology. The paper is titled “Coupling of receptor conformation and ligand orientation determine graded activity.”

Currently, ligands are considered to be the relatively static partner in the binding process and easily rejected if the protein dramatically changes shape. In contrast, working with the molecular systems that recognize the hormone estrogen, the Scripps study found that as protein receptors change shape, ligands can adapt to that change, binding productively to both active and inactive structures.

“To our great surprise, the ligand bound differently to the active and inactive conformations of the receptor,” notes Kendall Nettles, Ph.D., an associate professor in the department of cancer biology at Scripps Florida. “This strongly suggests a novel mechanism for managing cell-signaling activity. The implications of this are profound, both for our understanding of how ligands regulate protein activity, and as a novel approach in drug discovery.”

The Scripps team worked with an estrogen receptor and a well-known estrogen receptor antagonist. When ligands bind to a particular subset of receptors, they stabilize specific protein conformations, turning on or off molecular switches that control diverse cellular functions. For example, the binding of the breast cancer treatment tamoxifen is specific for the inactive conformation of the estrogen receptor; this locks the receptor in place, blocks the active conformation, and prevents tumor growth.

“Our new findings suggest that we need to think not only about an ensemble of protein conformations but also an ensemble of ligand-binding orientations when we think about therapeutic compounds,” explains Dr. Nettles. “As the protein and ligand move together, each can have a unique affinity and activity profile, which working together defines the signaling output.”

Dr. Nettles is excited by the possibility of working with an ensemble of ligand conformations, perhaps combining one with anti-inflammatory properties with another that blocks tumor growth. He will also work to find out whether the new study’s findings apply to other ligand-protein pairs. “If ligand dynamics turn out to be a general feature of small molecule signaling, then our findings have the potential to transform how we think about chemical biology.”

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