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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)29-34
Number of pages6
JournalNature Chemical Biology
Volume12
Issue number1
Early online date23 Nov 2015
DOIs
DateAccepted/In press - 7 Oct 2015
DateE-pub ahead of print - 23 Nov 2015
DatePublished (current) - Jan 2016

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.

    Structured keywords

  • Bristol BioDesign Institute

    Research areas

  • Circular Dichroism, Crystallography, X-Ray, Hydrogen Bonding, Models, Molecular, Protein Conformation, Protein Engineering, Protein Folding, Proteins, Chemical genetics, Target identification, Target validation, synthetic biology

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Nature at http://www.nature.com/nchembio/journal/v12/n1/full/nchembio.1966.html. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 2.8 MB, PDF document

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