A macrocyclic peptide that serves as a cocrystallization ligand and inhibits the function of a MATE family transporter

The random non-standard peptide integrated discovery (RaPID) system has proven to be a powerful approach to discover de novo natural product-like macrocyclic peptides that inhibit protein functions. We have recently reported three macrocyclic peptides that bind to Pyrococcus furiosus multidrug and t...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2013-08, Vol.18 (9), p.10514-10530
Main Authors: Hipolito, Christopher J, Tanaka, Yoshiki, Katoh, Takayuki, Nureki, Osamu, Suga, Hiroaki
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Antibodies
Antiporters - antagonists & inhibitors
Antiporters - chemistry
Archaeal Proteins - antagonists & inhibitors
Archaeal Proteins - chemistry
cocrystallization ligand
Crystallization
Crystallography, X-Ray
Drug Discovery
Drug resistance
Drug Resistance, Multiple
Escherichia coli
Ethidium - metabolism
Fluorescent Dyes - metabolism
Hydrophilic surfaces
in vitro selection
Libraries
Ligands
macrocyclic peptide
Medical research
Models, Molecular
Molecular Sequence Data
Peptides
Peptides, Cyclic - chemistry
Peptides, Cyclic - pharmacology
PfMATE
Protein Binding
Protein Structure, Secondary
Proteins
Pyrococcus furiosus - metabolism
random non-standard peptide integrated discovery (RaPID)
Ribonucleic acid
RNA
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Summary:The random non-standard peptide integrated discovery (RaPID) system has proven to be a powerful approach to discover de novo natural product-like macrocyclic peptides that inhibit protein functions. We have recently reported three macrocyclic peptides that bind to Pyrococcus furiosus multidrug and toxic compound extrusion (PfMATE) transporter and inhibit the transport function. Moreover, these macrocyclic peptides were successfully employed as cocrystallization ligands of selenomethionine-labeled PfMATE. In this report, we disclose the details of the RaPID selection strategy that led to the identification of these three macrocyclic peptides as well as a fourth macrocyclic peptide, MaD8, which is exclusively discussed in this article. MaD8 was found to bind within the cleft of PfMATE's extracellular side and blocked the path of organic small molecules being extruded. The results of an ethidium bromide efflux assay confirmed the efflux inhibitory activity of MaD8, whose behavior was similar to that of previously reported MaD5.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules180910514