How an e-mail got a structural biologist hooked on plants.
Four years after becoming head of a lab at the University of Washington in Seattle, Ning Zheng received an e-mail that opened up a whole new area of research. Up to that point, Zheng had been studying the structure and function of mammalian ubiquitin ligases, a family of enzymes. Now he is immersed in the world of plants.
The message was from plant biologist Mark Estelle at Indiana University in Bloomington. In 2005, Estelle identified the cell receptor in plants for the important hormone auxin. This hormone regulates growth in response to various environmental cues, although the mechanism behind its action has proved elusive.
The receptor identified by Estelle, called TIR1, was similar to the ubiquitin ligases that Zheng had been studying. “Right away we wanted to work on this new enzyme,” says Zheng. “But even before I wrote a message to Mark, I got an e-mail from him asking me to collaborate. I sent a response back within one minute: 'We are on board'.”
The scientists wanted to find out how auxin binding to TIR1 activated the cascade of chemical responses in plants. Usually enzymes such as ubiquitin ligases bind proteins that have been tagged with some kind of molecular modification. But auxin is a relatively small molecule — how could it mediate this? To complicate matters further, there are many naturally occurring and synthetic auxins, and despite being chemically different, they all elicit the same response.
Zheng's group began by trying to work out the crystal structure of TIR1. But the team was surprised to find an electron-dense region in the centre of the protein. Puzzled, Zheng telephoned his father, a retired biochemistry professor in China, to ask for advice. His father suggested that an inositol phosphate molecule might explain the structure and act as a co-factor for the enzyme's activity. Zheng confirmed the hunch using mass spectrometry, performed by researchers at the University of Cambridge, UK, earning his father a place in the list of authors on the paper on page 640 of this issue.
With this puzzle solved, the researchers went on to obtain the first glimpse of TIR1 bound to auxin. They found that TIR1 has a cavity on its surface and that by filling the cavity, auxin acts like a 'molecular glue' for TIR1 to bind tightly to its substrates.
Zheng's group went on to determine the structure of TIR1 bound to a number of different auxin analogues. In each case, the small molecules fit snugly into TIR1's pocket. “That explains why different molecules have the same effect,” says Zheng. “Anything that you can fit into that cavity between receptor and substrate will work to enhance their affinity.”
The finding has implications for drug discovery. Traditionally, scientists have tried to synthesize small molecules that inhibit interactions among proteins as a way of treating disease. But such approaches have had limited success. “It may be more feasible to use small molecules to promote interactions,” says Zheng, who now plans to test this idea. He also hopes to determine the structure of another plant hormone bound to its receptor. “I am totally into plants now,” he says. “I had ignored plant biology during graduate school and my postdoc, but now I am surrounded by plant-biology textbooks and papers.”
About this article
Cite this article
Ning Zheng. Nature 446, xiii (2007). https://doi.org/10.1038/7136xiiia