Design of functional metalloproteins

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Metalloproteins catalyse some of the most complex and important processes in nature, such as photosynthesis and water oxidation. An ultimate test of our knowledge of how metalloproteins work is to design new metalloproteins. Doing so not only can reveal hidden structural features that may be missing from studies of native metalloproteins and their variants, but also can result in new metalloenzymes for biotechnological and pharmaceutical applications. Although it is much more challenging to design metalloproteins than non-metalloproteins, much progress has been made in this area, particularly in functional design, owing to recent advances in areas such as computational and structural biology.

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Figure 1: Designed metalloproteins using de novo-designed scaffolds.
Figure 2: Designed metalloproteins using native scaffolds.
Figure 3: Site-specific incorporation of unnatural amino acids into a protein scaffold for the tuning of metalloprotein functional properties.
Figure 4: Examples of strategies for the incorporation of non-native metal cofactors into protein scaffolds.
Figure 5: Close match between a designed metalloprotein and its native target protein.

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We thank W. F. DeGrado, B. R. Gibney and P. L. Dutton for providing images used in Figure 1, N. Nagraj for help with editing the manuscript, and the US National Science Foundation (CHE 05-52008) and National Institutes of Health (GM062211) for financial support.

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Lu, Y., Yeung, N., Sieracki, N. et al. Design of functional metalloproteins. Nature 460, 855–862 (2009) doi:10.1038/nature08304

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