Rational protein design is an emerging ap- proach for testing general theories of protein chemistry through the creation of new structures and functions. Here we present the first successful introduction by rational design of a [Fe_4S_4] cuboidal cluster into the hydrophobic core of Escherichia coli thioredoxin, a protein normally devoid of metal centers. Cuboidal [Fe_4S_4] is one of the stable forms of self-assembled iron-sulfur clusters that are thought to rep- resent some of the earliest evolved biological redox centers.
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