Conservation and variability of the pore-lining helices in P-loop channels

Tikhonov, Denis B.; Zhorov, Boris S.

doi:10.1080/19336950.2017.1395536

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…As a result, the π-bulges would significantly change the structural stability of the entire pore domain and affect transitions between functional states of the channel. π-Bulges are seen in other P-loop channels, particularly in two-pore and TRP channels [35], but these channels are not the focus of the present study. Many available structures of TRP channels demonstrate a large diversity of π-bulges in S6 segments.…”

Section: Discussionmentioning

confidence: 88%

“…Moreover, at least two examples demonstrate structural rearrangements due to π-bulges, which are apparently induced by ligand binding (PDB IDs: 6kzo vs. 6kzp and 6jpa vs. 6jpb). Besides affecting ligand-channel interactions, π-bulges may dramatically change interactions between adjacent segments including helices S6, S5, and S4-S5 [ 35 ]. As a result, the π-bulges would significantly change the structural stability of the entire pore domain and affect transitions between functional states of the channel.…”

Section: Discussionmentioning

confidence: 99%

“…π-Bulges are seen in other P-loop channels, particularly in two-pore and TRP channels [ 35 ], but these channels are not the focus of the present study. Many available structures of TRP channels demonstrate a large diversity of π-bulges in S6 segments.…”

Section: Discussionmentioning

confidence: 99%

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Computational Analysis of the Crystal and Cryo-EM Structures of P-Loop Channels with Drugs

Tikhonov

Zhorov

2021

IJMS

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The superfamily of P-loop channels includes various potassium channels, voltage-gated sodium and calcium channels, transient receptor potential channels, and ionotropic glutamate receptors. Despite huge structural and functional diversity of the channels, their pore-forming domain has a conserved folding. In the past two decades, scores of atomic-scale structures of P-loop channels with medically important drugs in the inner pore have been published. High structural diversity of these complexes complicates the comparative analysis of these structures. Here we 3D-aligned structures of drug-bound P-loop channels, compared their geometric characteristics, and analyzed the energetics of ligand-channel interactions. In the superimposed structures drugs occupy most of the sterically available space in the inner pore and subunit/repeat interfaces. Cationic groups of some drugs occupy vacant binding sites of permeant ions in the inner pore and selectivity-filter region. Various electroneutral drugs, lipids, and detergent molecules are seen in the interfaces between subunits/repeats. In many structures the drugs strongly interact with lipid and detergent molecules, but physiological relevance of such interactions is unclear. Some eukaryotic sodium and calcium channels have state-dependent or drug-induced π-bulges in the inner helices, which would be difficult to predict. The drug-induced π-bulges may represent a novel mechanism of gating modulation.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Computational Analysis of the Crystal and Cryo-EM Structures of P-Loop Channels with Drugs

Tikhonov

Zhorov

2021

IJMS

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“…To compare different models, they were superposed by minimizing RMS deviations of alpha carbons in positions p38–p48 of the P1 helices (Table 1), which are the most 3D conserved segments in X-ray and cryo-EM structures of various P-loop channels (Tikhonov and Zhorov, 2017a).…”

Section: Methodsmentioning

confidence: 99%

Atomic Mechanisms of Timothy Syndrome-Associated Mutations in Calcium Channel Cav1.2

et al. 2019

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Timothy syndrome (TS) is a very rare multisystem disorder almost exclusively associated with mutations G402S and G406R in helix IS6 of Cav1.2. Recently, mutations R518C/H in helix IIS0 of the voltage sensing domain II (VSD-II) were described as a cause of cardiac-only TS. The three mutations are known to decelerate voltage-dependent inactivation (VDI). Here, we report a case of cardiac-only TS caused by mutation R518C. To explore possible impact of the three mutations on interdomain contacts, we modeled channel Cav1.2 using as templates Class Ia and Class II cryo-EM structures of presumably inactivated channel Cav1.1. In both models, R518 and several other residues in VSD-II donated H-bonds to the IS6-linked α1-interaction domain (AID). We further employed steered Monte Carlo energy minimizations to move helices S4–S5, S5, and S6 from the inactivated-state positions to those seen in the X-ray structures of the open and closed NavAb channel. In the open-state models, positions of AID and VSD-II were similar to those in Cav1.1. In the closed-state models, AID moved along the β subunit (Cavβ) toward the pore axis and shifted AID-bound VSD-II. In all the models R518 retained strong contacts with AID. Our calculations suggest that conformational changes in VSD-II upon its deactivation would shift AID along Cavβ toward the pore axis. The AID-linked IS6 would bend at flexible G402 and G406, facilitating the activation gate closure. Mutations R518C/H weakened the IIS0-AID contacts and would retard the AID shift. Mutations G406R and G402S stabilized the open state and would resist the pore closure. Several Cav1.2 mutations associated with long QT syndromes are consistent with this proposition. Our results provide a mechanistic rationale for the VDI deceleration caused by TS-associated mutations and suggest targets for further studies of calcium channelopathies.

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“…The 3D alignment was obtained by minimizing RMS deviations of alpha carbon atoms in residues, which according to the straightforward sequence alignment are in matching positions of the P1 helices ( Figure 5A ). The P1 helices are chosen for the 3D alignment because they are the most structurally conserved segments of P-loop channels ( Tikhonov and Zhorov, 2017a ).…”

Section: Homology Models Vs Cryo-em Structures Of Eukaryotic Sodium mentioning

confidence: 99%

Predicting Structural Details of the Sodium Channel Pore Basing on Animal Toxin Studies

Tikhonov

Zhorov

2018

Front. Pharmacol.

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Eukaryotic voltage-gated sodium channels play key roles in physiology and are targets for many toxins and medically important drugs. Physiology, pharmacology, and general architecture of the channels has long been the subject of intensive research in academia and industry. In particular, animal toxins such as tetrodotoxin, saxitoxin, and conotoxins have been used as molecular probes of the channel structure. More recently, X-ray structures of potassium and prokaryotic sodium channels allowed elaborating models of the toxin-channel complexes that integrated data from biophysical, electrophysiological, and mutational studies. Atomic level cryo-EM structures of eukaryotic sodium channels, which became available in 2017, show that the selectivity filter structure and other important features of the pore domain have been correctly predicted. This validates further employments of toxins and other small molecules as sensitive probes of fine structural details of ion channels.

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Conservation and variability of the pore-lining helices in P-loop channels

Cited by 10 publications

References 34 publications

Computational Analysis of the Crystal and Cryo-EM Structures of P-Loop Channels with Drugs

Computational Analysis of the Crystal and Cryo-EM Structures of P-Loop Channels with Drugs

Atomic Mechanisms of Timothy Syndrome-Associated Mutations in Calcium Channel Cav1.2

Predicting Structural Details of the Sodium Channel Pore Basing on Animal Toxin Studies

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