Structures of human ENT1 in complex with adenosine reuptake inhibitors

Wright, Nicholas J.; Lee, Seok-Yong

doi:10.1038/s41594-019-0245-7

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

Journal Article · 24 June 2019 · Nature Structural & Molecular Biology

DOI: https://doi.org/10.1038/s41594-019-0245-7 · OSTI ID:1544863

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^[1]

Duke Univ. Medical Center, Durham, NC (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1544863

Journal Information:: Nature Structural & Molecular Biology, Journal Name: Nature Structural & Molecular Biology Journal Issue: 7 Vol. 26; ISSN 1545-9993

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Molecular predictors of gemcitabine response in pancreatic cancer Voutsadakis, Ioannis A. World Journal of Gastrointestinal Oncology, Vol. 3, Issue 11 https://doi.org/10.4251/wjgo.v3.i11.153	journal	January 2011
Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters Johnson, Zachary Lee; Lee, Jun-Ho; Lee, Kiyoun eLife, Vol. 3 https://doi.org/10.7554/eLife.03604	journal	July 2014

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The genetic landscape of the human solute carrier (SLC) transporter superfamily Schaller, Lena; Lauschke, Volker M. Human Genetics, Vol. 138, Issue 11-12 https://doi.org/10.1007/s00439-019-02081-x	journal	November 2019
Current Progress on Equilibrative Nucleoside Transporter Function and Inhibitor Design Rehan, Shahid; Shahid, Saman; Salminen, Tiina A. SLAS DISCOVERY: Advancing the Science of Drug Discovery, Vol. 24, Issue 10 https://doi.org/10.1177/2472555219870123	journal	September 2019
Adenosine Receptor Profiling Reveals an Association between the Presence of Spare Receptors and Cardiovascular Disorders Fenouillet, Emmanuel; Mottola, Giovanna; Kipson, Nathalie International Journal of Molecular Sciences, Vol. 20, Issue 23 https://doi.org/10.3390/ijms20235964	journal	November 2019

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