The structure of chagasin in complex with a cysteine protease clarifies the binding mode and evolution of an inhibitor family |
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Authors: | Wang Stephanie X Pandey Kailash C Scharfstein Julio Whisstock James Huang Rick K Jacobelli Jordan Fletterick Robert J Rosenthal Philip J Abrahamson Magnus Brinen Linda S Rossi Andrea Sali Andrej McKerrow James H |
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Affiliation: | Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. |
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Abstract: | Protein inhibitors of proteolytic enzymes regulate proteolysis and prevent the pathological effects of excess endogenous or exogenous proteases. Cysteine proteases are a large family of enzymes found throughout the plant and animal kingdoms. Disturbance of the equilibrium between cysteine proteases and natural inhibitors is a key event in the pathogenesis of cancer, rheumatoid arthritis, osteoporosis, and emphysema. A family (I42) of cysteine protease inhibitors (http://merops.sanger.ac.uk) was discovered in protozoan parasites and recently found widely distributed in prokaryotes and eukaryotes. We report the 2.2 A crystal structure of the signature member of the I42 family, chagasin, in complex with a cysteine protease. Chagasin has a unique variant of the immunoglobulin fold with homology to human CD8alpha. Interactions of chagasin with a target protease are reminiscent of the cystatin family inhibitors. Protein inhibitors of cysteine proteases may have evolved more than once on nonhomologous scaffolds. |
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