When Ning Zheng got side-tracked from his studies of protein degradation, he never expected to end up in the plant world. Today, Zheng, associate professor of pharmacology at the University of Washington and an HHMI investigator, runs a triplicate of research agendas, all rooted in Xray Crystallography, and all aiming to find new therapeutic drugs for human diseases.
Zheng started his career solving large protein-protein complexes of ubiquitin ligases and the proteins they bind with to degrade them. Malfunctions in this process of ubiquitination are involved in several diseases including cancers, neurological disorders and viral infections. “A lot of companies are trying to find small molecules to manipulate ubiquitin ligases, but nobody has succeeded,” says Zheng.
In 2005, Zheng got side-tracked. A group in Indiana discovered that a plant hormone called auxin, which regulates plant growth, binds directly with ubiquitin ligase to regulate protein degradation. One year later, Zheng solved the structure of this complex.
By doing so, he discovered a surprising phenomenon. He found that the plant ubiquitin ligase and its target protein have an imperfect interface. Auxin, says Zheng, acts like “molecular glue” by filling in the gaps in this weak binding and allowing the proteins to bind with high affinity.
Zheng is now trying to translate this finding to human pathology, where mutations in human ubiquitin ligases cause low affinity bindings to target proteins. “The idea of using a small molecule, like auxin, to rescue a protein-protein interaction is new in the pharmaceutical industry,” says Zheng.
Once Zheng added the study of small molecules to his repertoire, his research took yet another side road. “All of the sudden science led us to study surface membrane proteins, including hormone receptors and ion channels,” says Zheng. “Most drug targets are on the membrane.”
Zheng, being a membrane protein rookie, had what he calls a stroke of beginners luck when he and his team solved the structure for a voltage-gated sodium channel, a channel others in the field had long been working to solve. “We took a new approach, with crazy ideas,” says Zheng. “SBGrid also helped us. Their software is now available to us and we used it for analyzing these membrane proteins.”
This work, published in the journal Nature, may help drive the discovery of new drugs such as local anesthetics and antiarrhythmics, which directly target this ion channel. Meanwhile, Zheng will let science be his guide.
– Elizabeth Dougherty