After more than 20 years, scientists have solved the full-length structure of a Janus kinase sciencemagazine
Researchers knew the shape of parts of the proteins, including related enzyme and regulatory regions at the end of the molecule, which earned them the name Janus kinases, after the two-faced mythological Roman god. And sophisticated drug screens have unearthed molecules that inhibit these proteins, giving doctors a way to treat some cancers and disorders like rheumatoid arthritis. But scientists developed the drugs without knowing the molecules' full structure or how they become activated.
In the last few years, the pieces began to fall into place. One key advance was a method called cryo-EM, where scientists freeze samples and then view them using an electron microscope. Another was the choice by Garcia's team to study a mouse Janus kinase rather than a less stable human one. They also introduced a common cancer-causing mutation into the mouse kinase, which stabilized the molecule even further.
The structure also reveals how the cancer-causing mutation short-circuits this messaging chain—by gluing two parts of the Janus kinase together. That causes the two active regions to stay switched on even when there are no outside cytokines, sparking uncontrolled activity that can trigger cancers.
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