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The structure of chagasin in complex with a cysteine protease clarifies the binding mode and evolution of an inhibitor family
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
Affiliation:Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
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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