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Publication - Dr Fabio Parmeggiani

    De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy

    Citation

    Huang, P-S, Feldmeier, K, Parmeggiani, F, Velasco, DAF, Höcker, B & Baker, D, 2016, ‘De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy’. Nature Chemical Biology, vol 12., pp. 29-34

    Abstract

    Despite efforts for over 25 years, de novo protein design has not succeeded in achieving the TIM-barrel fold. Here we describe the computational design of four-fold symmetrical (β/α)8 barrels guided by geometrical and chemical principles. Experimental characterization of 33 designs revealed the importance of side chain-backbone hydrogen bonds for defining the strand register between repeat units. The X-ray crystal structure of a designed thermostable 184-residue protein is nearly identical to that of the designed TIM-barrel model. PSI-BLAST searches do not identify sequence similarities to known TIM-barrel proteins, and sensitive profile-profile searches indicate that the design sequence is distant from other naturally occurring TIM-barrel superfamilies, suggesting that Nature has sampled only a subset of the sequence space available to the TIM-barrel fold. The ability to design TIM barrels de novo opens new possibilities for custom-made enzymes.

    Full details in the University publications repository