Scientists from The Scripps Research Institute have uncovered new evidence that challenges the current theory about a process key to the way modern drugs are designed and how they work in the human body. The new study was published October 10, 2010 in an advance, online edition of the journal Nature Chemical Biology.

Currently, the theory about ligands（配体） – compounds that bind¹ to proteins and trigger a specific biological action – and how they bind to proteins runs along the lines of a one person-one vote paradigm²（范例，典范） . Ligands are considered to be the relatively³ static partner in the process, and easily rejected if the protein dramatically changes shape.

In contrast, working with the molecular⁴ systems that recognize the hormone⁵ estrogen（雌性激素） , the new Scripps Research study found that as protein receptors change shape ligands can adapt to that change, binding⁶ productively to both active and inactive structures.

"To our great surprise, the ligand bound differently to the active and inactive conformations of the receptor," said Kendall Nettles⁷, an associate professor in the Department of Cancer Biology at Scripps Florida. "This strongly suggests a novel mechanism⁸ 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."

Changing the Drug Discovery Model

In the current study, the scientists worked with a receptor (which binds⁹ substances triggering certain biological effects) for the hormone estrogen and a well known estrogen receptor antagonist（敌手，对抗肌） (which blocks the receptor). Estrogen receptors are activated¹⁰ by the hormone estrogen, which is one of two primary female sex hormones¹¹ (the other is progesterone黄体酮). Disturbances¹² in estrogen levels play a role in number of disorders¹³ including cancers, heart disease, and stroke in women.

When ligands bind to a specific subset of receptors, the ligands stabilize¹⁴ specific protein conformations, turning on (or off) molecular switches that control diverse cellular¹⁵ functions. For example, the binding of the breast cancer treatment tamoxifen（三苯氧胺） is specific for the inactive conformation of the estrogen receptor – this locks the receptor in place, blocks the active conformation and prevents tumor¹⁶ growth.

"Our new findings suggest that we need to think not only about an ensemble¹⁷（全体，总效果） of protein conformations, but also an ensemble of ligand binding orientations¹⁸ when we think about therapeutic¹⁹ compounds," Nettles said. "As the protein and ligand move together, each can have a unique affinity²⁰（密切关系） , and activity profile, which working together defines the signaling output."

Nettles is excited by the possibility the new study suggests of working with an ensemble of ligand conformations, perhaps combining one with anti-inflammatory properties – which play a role in cancer – with another that blocks tumor growth. "This would give you dual²¹ therapeutic activity, potentially doubling the effectiveness of the treatment," he said.

Nettles is also eager to find out whether the new study's findings apply to other ligand-protein pairs. "If ligand dynamics²² turn out to be a general feature of small molecule²³ signaling," he said, "then our findings have the potential to transform how we think about chemical biology."