Screening, large-scale production and structure-based classification of cystine-dense peptides

Nature Structural & Molecular Biology
Colin E CorrentiRoland K Strong

Abstract

Peptides folded through interwoven disulfides display extreme biochemical properties and unique medicinal potential. However, their exploitation has been hampered by the limited amounts isolatable from natural sources and the expense of chemical synthesis. We developed reliable biological methods for high-throughput expression, screening and large-scale production of these peptides: 46 were successfully produced in multimilligram quantities, and >600 more were deemed expressible through stringent screening criteria. Many showed extreme resistance to temperature, proteolysis and/or reduction, and all displayed inhibitory activity against at least 1 of 20 ion channels tested, thus confirming their biological functionality. Crystal structures of 12 confirmed proper cystine topology and the utility of crystallography to study these molecules but also highlighted the need for rational classification. Previous categorization attempts have focused on limited subsets featuring distinct motifs. Here we present a global definition, classification and analysis of >700 structures of cystine-dense peptides, providing a unifying framework for these molecules.

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Citations

Aug 29, 2018·Protein Science : a Publication of the Protein Society·Garry W BuchkoChristopher D Bahl
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Methods Mentioned

BETA
reverse-phase chromatography
NMR
X-ray
transfection
flow cytometry

Software Mentioned

MEME
Geneious
PROMALS3D
COOT
REFMAC
Excel
CLUSTALW
SHELX
CCP4
PHASER

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