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Title: Structures of human ENT1 in complex with adenosine reuptake inhibitors

Abstract

The human equilibrative nucleoside transporter 1 (hENT1), a member of the SLC29 family, plays crucial roles in adenosine signaling, cellular uptake of nucleoside for DNA and RNA synthesis, and nucleoside-derived anticancer and antiviral drug transport in humans. Because of its central role in adenosine signaling, it is the target of adenosine reuptake inhibitors (AdoRI), several of which are used clinically. Despite its importance in human physiology and pharmacology, the molecular basis of hENT1-mediated adenosine transport and its inhibition by AdoRIs are limited, owing to the absence of structural information on hENT1. As such, here, we present crystal structures of hENT1 in complex with two chemically distinct AdoRIs: dilazep and S-(4-nitrobenzyl)-6-thioinosine (NBMPR). Combined with mutagenesis study, our structural analyses elucidate two distinct inhibitory mechanisms exhibited on hENT1 and provide insight into adenosine recognition and transport. Our studies provide a platform for improved pharmacological intervention of adenosine and nucleoside analog drug transport by hENT1.

Authors:
ORCiD logo [1]; ORCiD logo [1]
  1. Duke Univ. Medical Center, Durham, NC (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1544863
Grant/Contract Number:  
[P41GM103403; S10 RR029205]
Resource Type:
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
[ Journal Volume: 26; Journal Issue: 7]; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Membrane proteins; X-ray crystallography

Citation Formats

Wright, Nicholas J., and Lee, Seok-Yong. Structures of human ENT1 in complex with adenosine reuptake inhibitors. United States: N. p., 2019. Web. doi:10.1038/s41594-019-0245-7.
Wright, Nicholas J., & Lee, Seok-Yong. Structures of human ENT1 in complex with adenosine reuptake inhibitors. United States. doi:10.1038/s41594-019-0245-7.
Wright, Nicholas J., and Lee, Seok-Yong. Mon . "Structures of human ENT1 in complex with adenosine reuptake inhibitors". United States. doi:10.1038/s41594-019-0245-7.
@article{osti_1544863,
title = {Structures of human ENT1 in complex with adenosine reuptake inhibitors},
author = {Wright, Nicholas J. and Lee, Seok-Yong},
abstractNote = {The human equilibrative nucleoside transporter 1 (hENT1), a member of the SLC29 family, plays crucial roles in adenosine signaling, cellular uptake of nucleoside for DNA and RNA synthesis, and nucleoside-derived anticancer and antiviral drug transport in humans. Because of its central role in adenosine signaling, it is the target of adenosine reuptake inhibitors (AdoRI), several of which are used clinically. Despite its importance in human physiology and pharmacology, the molecular basis of hENT1-mediated adenosine transport and its inhibition by AdoRIs are limited, owing to the absence of structural information on hENT1. As such, here, we present crystal structures of hENT1 in complex with two chemically distinct AdoRIs: dilazep and S-(4-nitrobenzyl)-6-thioinosine (NBMPR). Combined with mutagenesis study, our structural analyses elucidate two distinct inhibitory mechanisms exhibited on hENT1 and provide insight into adenosine recognition and transport. Our studies provide a platform for improved pharmacological intervention of adenosine and nucleoside analog drug transport by hENT1.},
doi = {10.1038/s41594-019-0245-7},
journal = {Nature Structural & Molecular Biology},
number = [7],
volume = [26],
place = {United States},
year = {2019},
month = {6}
}

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