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1000
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Abstract/Summary
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The prototypical proprotein convertase furin proteolytically activates many precursor proteins and is essential for cellular homeostasis of the cell. Furin and other proprotein convertase are also associated with a number of diseases, including cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases. A hallmark of furin and its physiologic function is its stringent specificity for polybasic substrates. Here we describe several structural states of the protein by X-ray crystallography and further characterize them by molecular dynamics simulations. The transition between these conformers is triggered by substrate binding and calcium ligation, respectively, and helps explain the stringent specificity of furin and its functional features. These studies may pave the way for novel strategies of structure-guided inhibitor development.
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