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

Huang, P, Feldmeier, K, Parmeggiani, F ORCID: https://orcid.org/0000-0001-8548-1090, Velasco, D, Hoecker, B and Baker, D 2015. De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy. Nature Chemical Biology 12 (1) , pp. 29-34. 10.1038/nchembio.1966

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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 (beta/alpha)(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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	Nature Research
ISSN:	1552-4450
Last Modified:	17 Oct 2024 15:30
URI:	https://orca.cardiff.ac.uk/id/eprint/172215

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