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| Three-dimensional structure of the normal, inactive form of the FLT3 protein (forward, right) compared to proposed structure of mutated, active form of the protein (rear, left). Image courtesy Molecular Cell. |
Scientists have figured out the three-dimensional structure of a protein involved in leukemia. The structure shows how known mutations may cause the protein to be overactive. When this happens, blood cells can’t stop growing and leukemia can result. The researchers are using the information to design new drugs to shut the protein down.
Normally, the protein, called FLT3, becomes active when cells need to proliferate, and switches off when its job is done. However, certain mutations can put the protein in a permanently active state.
Researchers at Vertex Pharmaceuticals in Cambridge, Massachusetts, looked at the FLT3 protein in its inactive state. They zeroed in on regions of the protein in which activating mutations frequently occur.
They found that one of these regions serves as a sort of wedge that locks the protein in an inactive state. However, some mutant forms of the protein contain an extra stretch of the protein chain in this region. From looking at the structure, the researchers could see that an extra bit of protein would prevent the wedge from forming. Without the wedge, the protein is always active.
“Normally the active site is plugged up,” says James Griffith, who led the study. “If you have an extra insertion in this region of the protein, the domain can’t fold up properly and you have no wedge to plug up the active site. It’s just active all the time.”
The structure also suggests a second way that the protein might behave aberrantly. Normally, two molecules of FLT3 come together and activate each other when cells need to divide.
But Griffith noticed that the addition of the stretch of protein to the wedge area, which occurs in some mutant proteins, allows the protein to activate itself.
“In a normal protein, it’s almost like the protein can’t ‘scratch’ itself so it uses its neighbor,” says Griffith. “But the mutation allows the protein to scratch itself. It becomes active without any outside help.”
Thus, says Griffith, adding the extra stretch of protein in certain mutant forms of FLT3 serves as a double whammy. It prevents the formation of the wedge that keeps it in an inactive form and it allows the protein to activate itself.
The FLT3 protein is active in a wide range of leukemias. One third of all leukemia patients have a form of leukemia called acute myelogenous leukemia (AML) and as many as 40 percent of those patients have mutations that activate the FLT3 protein. Last year 7,800 patients died from AML, according to the American Cancer Society.
Griffith and his colleagues are now using the structure to design new drugs that would keep the FLT3 protein in an inactive state, and, they hope, lead to new treatments for the deadly disease.
