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

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

1
, 2,†
, 1
, 2,*  and 1,*
Received: 18 June 2013; in revised form: 24 August 2013 / Accepted: 27 August 2013 / Published: 30 August 2013
(This article belongs to the Special Issue Macrocyclic Chemistry)
Download PDF [991 KB, uploaded 18 June 2014]
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.
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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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.

AMA Style

Hipolito CJ, 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(9):10514-10530.

Chicago/Turabian Style

Hipolito, Christopher J.; Tanaka, Yoshiki; Katoh, Takayuki; Nureki, Osamu; Suga, Hiroaki. 2013. "A Macrocyclic Peptide that Serves as a Cocrystallization Ligand and Inhibits the Function of a MATE Family Transporter." Molecules 18, no. 9: 10514-10530.


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