4.8 Article

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

Journal

NATURE CHEMICAL BIOLOGY
Volume 12, Issue 1, Pages 29-+

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1966

Keywords

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Funding

  1. Direccion General de Asuntos del Personal Academico UNAM
  2. International Max Planck Research School (IMPRS) From Molecules to Organisms Tubingen
  3. Human Frontier Science Program Long-term fellowship [LT000070/2009-1]
  4. US National Science Foundation
  5. US Department of Energy's Office of Science
  6. Defense Threat Reduction Agency (DTRA)
  7. Howard Hughes Medical Institute
  8. Deutsche Forschungsgemeinschaft grant [HO4022/1-2]
  9. Max Planck funds
  10. CONACYT [99857]
  11. PAPIIT-UNAM [IN219913]

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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.

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