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

Huang, P-S; Feldmeier, K; Parmeggiani, F; Fernandez Velasco, DA; Höcker, B; Baker, D

doi:10.1038/nchembio.1966

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

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Feldmeier, K
IMPRS From Molecules to Organisms, Max Planck Institute for Developmental Biology, Max Planck Society;

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Höcker, B
Research Group Protein Design, Max Planck Institute for Developmental Biology, Max Planck Society;

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Citation

Huang, P.-S., Feldmeier, K., Parmeggiani, F., Fernandez Velasco, D., Höcker, B., & Baker, D. (2016). De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy. Nature Chemical Biology, 12(1), 29-34. doi:10.1038/nchembio.1966.

Cite as: https://hdl.handle.net/21.11116/0000-000A-7C5A-7

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.