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Philos Trans R Soc Lond B Biol Sci. 2017 Aug 5;372(1726). pii: 20160213. doi: 10.1098/rstb.2016.0213.

Membrane-spanning α-helical barrels as tractable protein-design targets.

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School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK
School of Biochemistry, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.
BrisSynBio, University of Bristol, Life Sciences Building, Tyndall Avenue, Bristol BS8 1TQ, UK.


The rational (de novo) design of membrane-spanning proteins lags behind that for water-soluble globular proteins. This is due to gaps in our knowledge of membrane-protein structure, and experimental difficulties in studying such proteins compared to water-soluble counterparts. One limiting factor is the small number of experimentally determined three-dimensional structures for transmembrane proteins. By contrast, many tens of thousands of globular protein structures provide a rich source of 'scaffolds' for protein design, and the means to garner sequence-to-structure relationships to guide the design process. The α-helical coiled coil is a protein-structure element found in both globular and membrane proteins, where it cements a variety of helix-helix interactions and helical bundles. Our deep understanding of coiled coils has enabled a large number of successful de novo designs. For one class, the α-helical barrels-that is, symmetric bundles of five or more helices with central accessible channels-there are both water-soluble and membrane-spanning examples. Recent computational designs of water-soluble α-helical barrels with five to seven helices have advanced the design field considerably. Here we identify and classify analogous and more complicated membrane-spanning α-helical barrels from the Protein Data Bank. These provide tantalizing but tractable targets for protein engineering and de novo protein design.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'.


coiled coil; de novo protein design; transmembrane proteins; α-helical barrel

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