Molecular mechanism underlying the subtype-selectivity of competitive inhibitor NF110 and its distinct potencies in human and rat P2X3 receptors

Li, Bin; Wang, Jin; Cheng, Xiaoyang; Liu, Yan; Yang, Yang; Yang, Xingyuan; Guo, Chengjun; Niu, Youya; Cao, Peng; Lu, Xiangyang; Zhu, Michael X.; Tian, Yun; Yu, Ye

doi:10.1016/j.scib.2018.11.016

Cited by 19 publications

(13 citation statements)

References 48 publications

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“…As described previously [ 51 , 52 ], DESMOND [ 53 ] was used to perform MD analysis with a constant number of particles, constant pressure (1 bar) and temperature (300 K) (NPT), and periodic boundary conditions (PBCs) by using the Nose–Hoover chain thermostat and Martyna–Tobias–Klein barostat methods. The MgtE TM domain dimer was embedded in a phosphoryl-oleoyl phosphatidylcholine (POPC) bilayer.…”

Section: Methodsmentioning

confidence: 99%

The structure of MgtE in the absence of magnesium provides new insights into channel gating

Jin¹,

Sun²,

Fujii

et al. 2021

PLoS Biol

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MgtE is a Mg2+ channel conserved in organisms ranging from prokaryotes to eukaryotes, including humans, and plays an important role in Mg2+ homeostasis. The previously determined MgtE structures in the Mg2+-bound, closed-state, and structure-based functional analyses of MgtE revealed that the binding of Mg2+ ions to the MgtE cytoplasmic domain induces channel inactivation to maintain Mg2+ homeostasis. There are no structures of the transmembrane (TM) domain for MgtE in Mg2+-free conditions, and the pore-opening mechanism has thus remained unclear. Here, we determined the cryo-electron microscopy (cryo-EM) structure of the MgtE-Fab complex in the absence of Mg2+ ions. The Mg2+-free MgtE TM domain structure and its comparison with the Mg2+-bound, closed-state structure, together with functional analyses, showed the Mg2+-dependent pore opening of MgtE on the cytoplasmic side and revealed the kink motions of the TM2 and TM5 helices at the glycine residues, which are important for channel activity. Overall, our work provides structure-based mechanistic insights into the channel gating of MgtE.

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Section: Methodsmentioning

confidence: 99%

The structure of MgtE in the absence of magnesium provides new insights into channel gating

Jin¹,

Sun²,

Fujii

et al. 2021

PLoS Biol

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“…The threshold for rejecting minimized poses was 0.5 kcal/mol. Docking scores and M085/GSK1702934A-residue interaction scores were summarized, sorted, and then plotted using Maestro ( 51 , 52 ).…”

Section: Methodsmentioning

confidence: 99%

GSK1702934A and M085 directly activate TRPC6 via a mechanism of stimulating the extracellular cavity formed by the pore helix and transmembrane helix S6

Yang

Wang

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…During gap-free recordings, the membrane potential was held at -60 mV and the ATP solution was applied with the Y-tube. As we previously described (19,48), nystatin-perforated patch clamp was carried out to reduce the dialysis of intracellular constituents and current rundown. Nystatin-perforated intracellular solution contains (in mM) 75 K 2 SO 4 , 55 KCl, 5 MgSO 4 , and 10 HEPES (pH 7.2).…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

A conserved residue in the P2X4 receptor has a nonconserved function in ATP recognition

Chen

Sun

et al. 2021

Journal of Biological Chemistry

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Molecular mechanism underlying the subtype-selectivity of competitive inhibitor NF110 and its distinct potencies in human and rat P2X3 receptors

Cited by 19 publications

References 48 publications

The structure of MgtE in the absence of magnesium provides new insights into channel gating

The structure of MgtE in the absence of magnesium provides new insights into channel gating

GSK1702934A and M085 directly activate TRPC6 via a mechanism of stimulating the extracellular cavity formed by the pore helix and transmembrane helix S6

A conserved residue in the P2X4 receptor has a nonconserved function in ATP recognition

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