Structural studies of ion channels: achievements, problems and perspectives

Мұқаба

Дәйексөз келтіру

Толық мәтін

Ашық рұқсат Ашық рұқсат
Рұқсат жабық Рұқсат берілді
Рұқсат жабық Тек жазылушылар үшін

Аннотация

The superfamily of membrane proteins known as P-loop channels encompasses potassium, sodium, and calcium channels, as well as TRP channels and ionotropic glutamate receptors. An increasing number of crystal and cryo-EM structures are uncovering both general and specific features of these channels. Fundamental folding principles, the arrangement of structural segments, key residues that influence ionic selectivity, gating, and binding sites for toxins and medically relevant ligands have now been firmly established. The advent of AlphaFold2 (AF2) models represents another significant step in computationally predicting protein structures. Comparison of experimental P-loop channel structures with their corresponding AF2 models shows consistent folding patterns in experimentally resolved regions. Despite this remarkable progress, many crucial structural details, particularly important for predicting the outcomes of mutations and designing new medically relevant ligands, remain unresolved. Certain methodological challenges currently hinder the direct assessment of such details. Until the next methodological breakthrough occurs, a promising approach to analyzing ion channel structures in greater depth involves integrating various experimental and theoretical methods.

Толық мәтін

Рұқсат жабық

Авторлар туралы

B. Zhorov

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences; McMaster University

Email: denistikhonov2002@yahoo.com

Department of Biochemistry and Biomedical Sciences, McMaster University

Ресей, St. Petersburg, 194223; Hamilton, Canada

D. Tikhonov

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Хат алмасуға жауапты Автор.
Email: denistikhonov2002@yahoo.com
Ресей, St. Petersburg, 194223

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2. Fig. 1. Diversity of the structural organization of P-loop channels and conservation of their pore-forming domains. a – The transmembrane topology of the TRP subunit and the 6-TM potassium channel (KV) differs from that of the glutamate receptor (GluR) subunit, including the opposite orientation of the P-loop. b – The overall architecture and domain organization of TRP, glutamate receptors, and 6-TM potassium channels are completely different. PD – pore-forming domain. c – Superposition of the pore-forming domains reveals their high similarity. The structures of 6dm0, 6ebk, and 6bcj are shown in blue, red, and green.

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3. Fig. 2. Diversity of activation rearrangements in the inner helices. a – view in the membrane plane, b – lateral projection. The closed state of KcsA (1bl8) is shown in red. In the open states of MthK (1lnq), KvAP (1orq), AMPA-type glutamate receptor (5weo), Kv1.2 (2r9r) and TRPV6 (6bo8), the inner helices are shown in purple, orange, yellow, blue and green, respectively.

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4. Fig. 3. Ligand binding in P-loop channels. a – Tetrabutylammonium binds in the central cavity of KcsA. b – Scorpion venom peptide toxin binds to the voltage-sensing domain of the sodium channel. c – Tetrodotoxin binds in the outer vestibule of the sodium channel. d – Flecainide binds in the central cavity of the sodium channel. d – IEM-1460 binds in the outer vestibule of the AMPA receptor channel and partially penetrates the selective filter.

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5. Fig. 4. Fully α-helical segments of TRPV3 (6mh0, red) and segments with π-helical elements (6uw4, green). a – The π-helical element in the helix appears as a bulge. b, c – Since the π-helix has an extra residue per turn, the presence of such an element causes a reorientation of residues in the C-part of the helix. The CA and CB atoms of the conserved asparagine residues are shown as spheres.

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6. Fig. 5. Lipid and detergent molecules interact with a verapamil molecule in the pore of a calcium channel.

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