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Molecules 2013, 18(9), 10514-10530; doi:10.3390/molecules180910514

A Macrocyclic Peptide that Serves as a Cocrystallization Ligand and Inhibits the Function of a MATE Family Transporter

1
Department of Chemistry, Graduate School of Science, the University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-0033, Japan
2
Department of Biophysics and Biochemistry, Graduate School of Science, the University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Current address: Department of Medical Chemistry and Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
*
Authors to whom correspondence should be addressed.
Received: 18 June 2013 / Revised: 24 August 2013 / Accepted: 27 August 2013 / Published: 30 August 2013
(This article belongs to the Special Issue Macrocyclic Chemistry)
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Abstract

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. View Full-Text
Keywords: in vitro selection; cocrystallization ligand; random non-standard peptide integrated discovery (RaPID); macrocyclic peptide; PfMATE in vitro selection; cocrystallization ligand; random non-standard peptide integrated discovery (RaPID); macrocyclic peptide; PfMATE
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MDPI and ACS Style

Hipolito, C.J.; Tanaka, Y.; Katoh, T.; Nureki, O.; Suga, H. A Macrocyclic Peptide that Serves as a Cocrystallization Ligand and Inhibits the Function of a MATE Family Transporter. Molecules 2013, 18, 10514-10530.

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