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Synthetic beta-solenoid proteins with the fragment-free computational design of a beta-hairpin extension

DOI: 10.1073/pnas.1525308113 DOI Help

Authors: James T. Macdonald (Imperial College London) , Burak V. Kabasakal (Imperial College London) , David Godding (Imperial College London; University of Cambridge) , Sebastian Kraatz (Imperial College London; Paul Scherrer Institut) , Louie Henderson (Imperial College London) , James Barber (Department of Life Sciences, Imperial College London) , Paul Freemont (Imperial College London) , James W. Murray (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 113 , PAGES 10346 - 10351

State: Published (Approved)
Published: September 2016
Diamond Proposal Number(s): 7299 , 1227 , 9424

Open Access Open Access

Abstract: The ability to design and construct structures with atomic level precision is one of the key goals of nanotechnology. Proteins offer an attractive target for atomic design because they can be synthesized chemically or biologically and can self-assemble. However, the generalized protein folding and design problem is unsolved. One approach to simplifying the problem is to use a repetitive protein as a scaffold. Repeat proteins are intrinsically modular, and their folding and structures are better understood than large globular domains. Here, we have developed a class of synthetic repeat proteins based on the pentapeptide repeat family of beta-solenoid proteins. We have constructed length variants of the basic scaffold and computationally designed de novo loops projecting from the scaffold core. The experimentally solved 3.56-Å resolution crystal structure of one designed loop matches closely the designed hairpin structure, showing the computational design of a backbone extension onto a synthetic protein core without the use of backbone fragments from known structures. Two other loop designs were not clearly resolved in the crystal structures, and one loop appeared to be in an incorrect conformation. We have also shown that the repeat unit can accommodate whole-domain insertions by inserting a domain into one of the designed loops.

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography


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