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Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2

Activation of the transient receptor potential melastatin 2 (TRPM2) channel occurs during the response to oxidative stress under physiological conditions as well as in pathological processes such as ischemia and diabetes. Accumulating evidence indicates that adenosine diphosphate ribose (ADPR) is th...

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Autores principales: Yu, Peilin, Xue, Xiwen, Zhang, Jianmin, Hu, Xupang, Wu, Yan, Jiang, Lin-Hua, Jin, Hongwei, Luo, Jianhong, Zhang, Liangren, Liu, Zhenming, Yang, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299621/
https://www.ncbi.nlm.nih.gov/pubmed/28108595
http://dx.doi.org/10.1085/jgp.201611675
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author Yu, Peilin
Xue, Xiwen
Zhang, Jianmin
Hu, Xupang
Wu, Yan
Jiang, Lin-Hua
Jin, Hongwei
Luo, Jianhong
Zhang, Liangren
Liu, Zhenming
Yang, Wei
author_facet Yu, Peilin
Xue, Xiwen
Zhang, Jianmin
Hu, Xupang
Wu, Yan
Jiang, Lin-Hua
Jin, Hongwei
Luo, Jianhong
Zhang, Liangren
Liu, Zhenming
Yang, Wei
author_sort Yu, Peilin
collection PubMed
description Activation of the transient receptor potential melastatin 2 (TRPM2) channel occurs during the response to oxidative stress under physiological conditions as well as in pathological processes such as ischemia and diabetes. Accumulating evidence indicates that adenosine diphosphate ribose (ADPR) is the most important endogenous ligand of TRPM2. However, although it is known that ADPR binds to the NUDT9 homology (NUDT9-H) domain in the intracellular C-terminal region, the molecular mechanism underlying ADPR binding and activation of TRPM2 remains unknown. In this study, we generate a structural model of the NUDT9-H domain and identify the binding pocket for ADPR using induced docking and molecular dynamics simulation. We find a subset of 11 residues—H1346, T1347, T1349, L1379, G1389, S1391, E1409, D1431, R1433, L1484, and H1488—that are most likely to directly interact with ADPR. Results from mutagenesis and electrophysiology approaches support the predicted binding mechanism, indicating that ADPR binds tightly to the NUDT9-H domain, and suggest that the most significant interactions are the van der Waals forces with S1391 and L1484, polar solvation interaction with E1409, and electronic interactions (including π–π interactions) with H1346, T1347, Y1349, D1431, and H1488. These findings not only clarify the roles of a range of newly identified residues involved in ADPR binding in the TRPM2 channel, but also reveal the binding pocket for ADPR in the NUDT9-H domain, which should facilitate structure-based drug design for the TRPM2 channel.
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spelling pubmed-52996212017-08-01 Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2 Yu, Peilin Xue, Xiwen Zhang, Jianmin Hu, Xupang Wu, Yan Jiang, Lin-Hua Jin, Hongwei Luo, Jianhong Zhang, Liangren Liu, Zhenming Yang, Wei J Gen Physiol Research Articles Activation of the transient receptor potential melastatin 2 (TRPM2) channel occurs during the response to oxidative stress under physiological conditions as well as in pathological processes such as ischemia and diabetes. Accumulating evidence indicates that adenosine diphosphate ribose (ADPR) is the most important endogenous ligand of TRPM2. However, although it is known that ADPR binds to the NUDT9 homology (NUDT9-H) domain in the intracellular C-terminal region, the molecular mechanism underlying ADPR binding and activation of TRPM2 remains unknown. In this study, we generate a structural model of the NUDT9-H domain and identify the binding pocket for ADPR using induced docking and molecular dynamics simulation. We find a subset of 11 residues—H1346, T1347, T1349, L1379, G1389, S1391, E1409, D1431, R1433, L1484, and H1488—that are most likely to directly interact with ADPR. Results from mutagenesis and electrophysiology approaches support the predicted binding mechanism, indicating that ADPR binds tightly to the NUDT9-H domain, and suggest that the most significant interactions are the van der Waals forces with S1391 and L1484, polar solvation interaction with E1409, and electronic interactions (including π–π interactions) with H1346, T1347, Y1349, D1431, and H1488. These findings not only clarify the roles of a range of newly identified residues involved in ADPR binding in the TRPM2 channel, but also reveal the binding pocket for ADPR in the NUDT9-H domain, which should facilitate structure-based drug design for the TRPM2 channel. The Rockefeller University Press 2017-02 /pmc/articles/PMC5299621/ /pubmed/28108595 http://dx.doi.org/10.1085/jgp.201611675 Text en © 2017 Yu et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Yu, Peilin
Xue, Xiwen
Zhang, Jianmin
Hu, Xupang
Wu, Yan
Jiang, Lin-Hua
Jin, Hongwei
Luo, Jianhong
Zhang, Liangren
Liu, Zhenming
Yang, Wei
Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2
title Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2
title_full Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2
title_fullStr Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2
title_full_unstemmed Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2
title_short Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2
title_sort identification of the adpr binding pocket in the nudt9 homology domain of trpm2
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299621/
https://www.ncbi.nlm.nih.gov/pubmed/28108595
http://dx.doi.org/10.1085/jgp.201611675
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