Geometric rules of channel gating inferred from computational models of the P2X receptor transmembrane domain

Li, Guohua

doi:10.1016/j.jmgm.2015.06.015

Cited by 2 publications

(5 citation statements)

References 27 publications

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“…Four major types of helix packing were identified in 23 independent MD simulations (60-150 ns) of TMD models (TMD-4DW0, TMD-4DW1 and TMD-5SVK) embedded in different lipid bilayers ( In the apo state models of the P2X receptor, the M2 helices cross in the outer portion at residue G343 that packs into a downstream pocket formed by A344, A347 and L348. In most simulations of the TMD-4DW0 model (n = 10 out of 17), the packing of G343 remains stable in different lipid environments [12]. A344 packs into an upstream pocket formed either by L339, L340 and G343 or by L340, G343 and A344 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…4A) and the L340 side-chain may also block the pore (Fig. 6A), depending on the side-chain orientation [12].…”

Section: Resultsmentioning

confidence: 99%

“…As in the previous report [12], ideal M1 (from S28 to D59) and M2 helices (from K332 to L361) are individually relaxed in POPC bilayers and assembled into a tertiary structure based on the 4DW0 model. The residues D59 and K332 are connected to form a loop.…”

Section: Tmd Models For MD Simulationsmentioning

confidence: 92%

“…The question I ask here is how different packing patterns between M2 helices associate with different conformational states of the P2X receptor. In a previous study [12], I investigated the packing patterns of the M2 helices in different lipid environments, including POPC, 1 -s t e a r o y l -2 -o l e o y l -s n -g l y c e r o -3 -p h o s p h o c h o l i n e ( S O P C ) a n d 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) bilayers. Changes in the pore geometry were interpreted as a result of knob into pocket packing, a concept discovered more than 50 years ago [13].…”

Section: Introductionmentioning

confidence: 88%

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Exploring conformational states and helical packings in the P2X receptor transmembrane domain by molecular dynamics simulation

2018

J Biol Phys

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The P2X receptor is a trimeric transmembrane protein that acts as an ATP-gated ion channel. Its transmembrane domain (TMD) contains only six helices and three of them, the M2 helices, line the ion conduction pathway. Here, using molecular dynamics simulation, I identify four conformational states of the TMD that are associated with four types of packing between M2 helices. Packing in the extracellular half of the M2 helix produces closed conformations, while packing in the intracellular half produces both open and closed conformations. State transition is observed and supports a mechanism where iris-like twisting of the M2 helices switches the location of helical packing between the extracellular and the intracellular halves of the helices. In addition, this twisting motion alters the position and orientation of residue side-chains relative to the pore and therefore influences the pore geometry and possibly ion permeation. Helical packing, on the other hand, may restrict the twisting motion and generate discrete conformational states.

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Section: Resultsmentioning

confidence: 99%

“…4A) and the L340 side-chain may also block the pore (Fig. 6A), depending on the side-chain orientation [12].…”

Section: Resultsmentioning

confidence: 99%

Section: Tmd Models For MD Simulationsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 88%

See 2 more Smart Citations

Exploring conformational states and helical packings in the P2X receptor transmembrane domain by molecular dynamics simulation

2018

J Biol Phys

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“…The functioning of P2X receptors has been the focus of numerous computational studies. ,− Some of them were devoted to characterize the binding of ATP and the conformational changes that accompany the close-to-open transition. Molecular dynamics simulations and normal-mode analysis of the closed structure were used to propose a model for the opening process .…”

Section: Introductionmentioning

confidence: 99%

Positively Charged Residues in the Head Domain of P2X4 Receptors Assist the Binding of ATP

Racigh

Ormazábal

Palma

et al. 2019

J. Chem. Inf. Model.

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P2X receptors are a family of trimeric cationic channels located in the membrane of mammalian cells. They open in response to the binding of ATP. The differences between the closed and open structures have been described in detail for some members of the family. However, the order in which the conformational changes take place as ATP enters the binding cleft, and the residues involved in the intermediate stages, are still unknown. Here, we present the results of umbrella sampling simulations aimed to elucidate the sequence of conformational changes that occur during the reversible binding of ATP to the P2X4 receptor. The simulations also provided information about the interactions that develop in the course of the process. In particular, they revealed the existence of a metastable state which assists the binding. This state is stabilized by positively charged residues located in the head domain of the receptor. Based on these findings, we propose a novel mechanism for the capture of ATP by P2X4 receptors.

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Geometric rules of channel gating inferred from computational models of the P2X receptor transmembrane domain

Cited by 2 publications

References 27 publications

Exploring conformational states and helical packings in the P2X receptor transmembrane domain by molecular dynamics simulation

Exploring conformational states and helical packings in the P2X receptor transmembrane domain by molecular dynamics simulation

Positively Charged Residues in the Head Domain of P2X4 Receptors Assist the Binding of ATP

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