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


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.

Submission Details

ID: 42WeVJh83

Submitter: Connie Wang

Submission Date: May 9, 2017, 10:34 p.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

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
Sequence Assay Result Units