果冻影院

Many processes in biology depend on how large biomolecules, called proteins, interact with smaller chemicals or 'small molecules'. These interactions are often described in terms of a 鈥榣ock-and-key鈥� binding, whereby small molecules (keys) fit snugly into ridges or groves on the protein surface (locks). While about 2/3 of proteins adopt well-defined 3D shapes associated with a specific function, many proteins, including those involved in human-, viral-, and plant biology, never adopt a single shape and instead rapidly interconvert between many shapes.

These proteins, called 'disordered proteins', lack long-lived 鈥榣ocks鈥� to which small molecule 鈥榢eys鈥� can bind, making them difficult to target in drug discovery programmes using traditional methods. In fact, disordered proteins have been considered "undruggable" due to their lack of classical long-lived binding pockets for drugs.

Frequently, scientists will use a method called nuclear magnetic resonance (NMR) spectroscopy to study small-molecule interactions with proteins. Traditionally, however, these methods have been insensitive to binding between small molecules and disordered proteins. BBSRC Discovery Fellow Gabriella Heller and Professor D. Flemming Hansen in the Department of Structural and Molecular Biology (Division of Biosciences)听have recently developed a new NMR-based strategy based on the effective linewidth of 19F signals to detect the binding between a small molecule and a disordered protein. Using this approach, they discovered that a small molecule not only interacts with a disordered protein听but does so in exceptionally dynamic ways, in stark contrast to the traditional 鈥榣ock-and-key鈥� binding mechanism.

Dr Heller, the first author on the manuscript states 鈥楴ot only can we experimentally detect binding to these 鈥渦ndruggable鈥� proteins, but we can also learn something interesting about the mechanism of this interaction - the small molecule moves very quickly in the bound state - it鈥檚 quite unusual鈥�.

Professor D. Flemming Hansen, the lead researcher, expresses excitement because 鈥榯his study opens a new interdisciplinary scientific discipline, which links physics, chemistry, biology, as well as medicine, and where focus the next years will be on understanding and exploiting the mechanisms by which small molecules interact to disordered proteins.鈥�

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Further Information:

• Research Group website
• Research Department of Structural and Molecular Biology
• Division of Biosciences

Image:

Targeting disordered and flexible proteins represents a novel drug discovery strategy. (a) Conformations of a rigid protein with well-defined grooves and pockets, which can act as binding sites. (b) A disordered protein, which rapidly interconverts between states and generally considered not to have 鈥榯raditional鈥� drug binding sites.