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


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.

Submission Details

ID: 42WeVJh83

Submitter: Connie Wang

Submission Date: July 31, 2017, 11:46 a.m.

Version: 1

Publication Details
Huang PS;Feldmeier K;Parmeggiani F;Velasco DAF;Höcker B;Baker D,Nat Chem Biol (2016) De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy. PMID:26595462
Additional Information

Study Summary

Number of data points 29
Proteins Triosephosphate isomerase
Unique complexes 29
Assays/Quantities/Protocols Experimental Assay: Tm
Libraries De novo design of symmetric TIM-barrel proteins

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Triosephosphate isomerase P00940 TPIS_CHICK
90.3 Triosephosphate isomerase P54714 TPIS_CANLF