Issue Date: July 25, 2011
The first X-ray structure of a membrane aspartyl protease helps explain how the enzyme does its difficult job: using water to catalyze proteolysis in cell membranes, which don’t suffer water gladly. The work could make it easier to learn additional mechanistic details, with possible drug discovery implications. Structures of other membrane proteases have been determined. But membrane aspartyl proteases, which are perhaps the most important medically, had not been analyzed. Jian Hu, Yi Xue, Sangwon Lee, and Ya Ha at Yale School of Medicine have now crystallized and structurally analyzed the aspartyl protease FlaK (shown; Nature, DOI: 10.1038/nature10218). The structure suggests that the protein needs to make a conformational change to catalyze proteolysis, but it may also suggest that the captured conformation is inactive, comments membrane protease expert Michael S. Wolfe of Harvard Medical School. Aquiring the difficult-to-obtain structure is nevertheless “an important first step” toward better understanding aspartyl proteases, he says. “It provides insight into how FlaK may be working” and a framework for developing mechanistic hypotheses that can be tested with mutational and other experiments.
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