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J Gen Physiol. 2017 Feb;149(2):219-235. doi: 10.1085/jgp.201611675. Epub 2017 Jan 20.

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

Author information

1
Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
2
Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, China.
3
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
4
School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, England, UK.
5
Department of Physiology and Neurobiology, Xinxiang Medical University, Henan 453003, China.
6
Sino-UK Brain Function Laboratory, Xinxiang Medical University, Henan 453003, China.
7
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China yangwei@zju.edu.cn zmliu@bjmu.edu.cn.
8
Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China yangwei@zju.edu.cn zmliu@bjmu.edu.cn.

Abstract

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.

PMID:
28108595
PMCID:
PMC5299621
DOI:
10.1085/jgp.201611675
[Indexed for MEDLINE]
Free PMC Article

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