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Navigating the structural landscape of de novo α-helical bundles

DOI: 10.1021/jacs.8b13354 DOI Help

Authors: Guto G. Rhys (University of Bristol) , Christopher W. Wood (University of Bristol) , Joseph L. Beesley (University of Bristol) , Nathan R. Zaccai (University of Bristol) , Antony Burton (University of Bristol; Princeton University) , R. Leo Brady (University of Bristol) , Andrew R. Thomson (University of Bristol; University of Glasgow) , Derek N. Woolfson (University of Bristol)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of The American Chemical Society

State: Published (Approved)
Published: May 2019

Abstract: The association of amphipathic α helices in water leads to α-helical-bundle protein structures. However, the driving force for this—the hydrophobic effect—is not specific and does not define the number or the orientation of helices in the associated state. Rather, this is achieved through deeper sequence-to-structure relationships, which are increas-ingly being discerned. For example, for one structurally extreme but nevertheless ubiquitous class of bundle—the α-helical coiled coils—relationships have been established that discriminate between all-parallel dimers, trimers and tetramers. Association states above this are known, as are antiparallel and mixed arrangements of the helices. However, these alternative states are less-well understood. Here, we describe a synthetic-peptide system that switches be-tween parallel hexamers and various up-down-up-down tetramers in response to single-amino-acid changes and solution conditions. The main accessible states of each peptide variant are characterized fully in solution and, in most cases, to high resolution with X-ray crystal structures. Analysis and inspection of these structures helps rationalize the different states formed. This navigation of the structural landscape of α-helical coiled coils above the dimers and tri-mers that dominate in nature has allowed us to design rationally a well-defined and hyperstable antiparallel coiled-coil tetramer (apCC-Tet). This robust de novo protein provides another scaffold for further structural and functional designs in protein engineering and synthetic biology.

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography