Conformational dynamics of a nicotinic receptor neurotransmitter site
Agonists enhance receptor activity by providing net-favorable binding energy to active over resting conformations, with efficiency (η) linking binding energy to gating. Previously, we showed that in nicotinic receptors, η-values are grouped into five structural pairs, correlating efficacy and affini...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/92418 |
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| author | Mrityunjay Singh Dinesh C Indurthi Lovika Mittal Anthony Auerbach Shailendra Asthana |
| author_facet | Mrityunjay Singh Dinesh C Indurthi Lovika Mittal Anthony Auerbach Shailendra Asthana |
| author_sort | Mrityunjay Singh |
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| description | Agonists enhance receptor activity by providing net-favorable binding energy to active over resting conformations, with efficiency (η) linking binding energy to gating. Previously, we showed that in nicotinic receptors, η-values are grouped into five structural pairs, correlating efficacy and affinity within each class, uniting binding with allosteric activation (Indurthi and Auerbach, 2023). Here, we use molecular dynamics (MD) simulations to investigate the low-to-high affinity transition (L→H) at the Torpedo α−δ nicotinic acetylcholine receptor neurotransmitter site. Using four agonists spanning three η-classes, the simulations reveal the structural basis of the L→H transition where: the agonist pivots around its cationic center (‘flip’), loop C undergoes staged downward displacement (‘flop’), and a compact, stable high-affinity pocket forms (‘fix’). The η derived from binding energies calculated in silico matched exact values measured experimentally in vitro. Intermediate states of the orthosteric site during receptor activation are apparent only in simulations, but could potentially be observed experimentally via time-resolved structural studies. |
| format | Article |
| id | doaj-art-d8d6d6a370fa4ab58f2e2f8a22bd7eee |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-d8d6d6a370fa4ab58f2e2f8a22bd7eee2024-12-18T15:46:02ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.92418Conformational dynamics of a nicotinic receptor neurotransmitter siteMrityunjay Singh0Dinesh C Indurthi1https://orcid.org/0000-0001-8837-5883Lovika Mittal2Anthony Auerbach3https://orcid.org/0000-0003-4151-860XShailendra Asthana4Computational Biophysics and CADD Group, Computational and Mathematical Biology Center,Translational Health Science and Technology Institute, Faridabad, IndiaDepartment of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, United StatesComputational Biophysics and CADD Group, Computational and Mathematical Biology Center,Translational Health Science and Technology Institute, Faridabad, IndiaDepartment of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, United StatesComputational Biophysics and CADD Group, Computational and Mathematical Biology Center,Translational Health Science and Technology Institute, Faridabad, IndiaAgonists enhance receptor activity by providing net-favorable binding energy to active over resting conformations, with efficiency (η) linking binding energy to gating. Previously, we showed that in nicotinic receptors, η-values are grouped into five structural pairs, correlating efficacy and affinity within each class, uniting binding with allosteric activation (Indurthi and Auerbach, 2023). Here, we use molecular dynamics (MD) simulations to investigate the low-to-high affinity transition (L→H) at the Torpedo α−δ nicotinic acetylcholine receptor neurotransmitter site. Using four agonists spanning three η-classes, the simulations reveal the structural basis of the L→H transition where: the agonist pivots around its cationic center (‘flip’), loop C undergoes staged downward displacement (‘flop’), and a compact, stable high-affinity pocket forms (‘fix’). The η derived from binding energies calculated in silico matched exact values measured experimentally in vitro. Intermediate states of the orthosteric site during receptor activation are apparent only in simulations, but could potentially be observed experimentally via time-resolved structural studies.https://elifesciences.org/articles/92418nicotinic receptorion channelallostery |
| spellingShingle | Mrityunjay Singh Dinesh C Indurthi Lovika Mittal Anthony Auerbach Shailendra Asthana Conformational dynamics of a nicotinic receptor neurotransmitter site eLife nicotinic receptor ion channel allostery |
| title | Conformational dynamics of a nicotinic receptor neurotransmitter site |
| title_full | Conformational dynamics of a nicotinic receptor neurotransmitter site |
| title_fullStr | Conformational dynamics of a nicotinic receptor neurotransmitter site |
| title_full_unstemmed | Conformational dynamics of a nicotinic receptor neurotransmitter site |
| title_short | Conformational dynamics of a nicotinic receptor neurotransmitter site |
| title_sort | conformational dynamics of a nicotinic receptor neurotransmitter site |
| topic | nicotinic receptor ion channel allostery |
| url | https://elifesciences.org/articles/92418 |
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