Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors.
The initial coupling between ligand binding and channel gating in the human alpha7 nicotinic acetylcholine receptor (nAChR) has been investigated with targeted molecular dynamics (TMD) simulation. During the simulation, eight residues at the tip of the C-loop in two alternating subunits were forced...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2006-09-01
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| Series: | PLoS Computational Biology |
| Online Access: | http://europepmc.org/articles/PMC1584325?pdf=render |
| _version_ | 1811268300625149952 |
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| author | Xiaolin Cheng Hailong Wang Barry Grant Steven M Sine J Andrew McCammon |
| author_facet | Xiaolin Cheng Hailong Wang Barry Grant Steven M Sine J Andrew McCammon |
| author_sort | Xiaolin Cheng |
| collection | DOAJ |
| description | The initial coupling between ligand binding and channel gating in the human alpha7 nicotinic acetylcholine receptor (nAChR) has been investigated with targeted molecular dynamics (TMD) simulation. During the simulation, eight residues at the tip of the C-loop in two alternating subunits were forced to move toward a ligand-bound conformation as captured in the crystallographic structure of acetylcholine binding protein (AChBP) in complex with carbamoylcholine. Comparison of apo- and ligand-bound AChBP structures shows only minor rearrangements distal from the ligand-binding site. In contrast, comparison of apo and TMD simulation structures of the nAChR reveals significant changes toward the bottom of the ligand-binding domain. These structural rearrangements are subsequently translated to the pore domain, leading to a partly open channel within 4 ns of TMD simulation. Furthermore, we confirmed that two highly conserved residue pairs, one located near the ligand-binding pocket (Lys145 and Tyr188), and the other located toward the bottom of the ligand-binding domain (Arg206 and Glu45), are likely to play important roles in coupling agonist binding to channel gating. Overall, our simulations suggest that gating movements of the alpha7 receptor may involve relatively small structural changes within the ligand-binding domain, implying that the gating transition is energy-efficient and can be easily modulated by agonist binding/unbinding. |
| first_indexed | 2024-04-12T21:19:11Z |
| format | Article |
| id | doaj.art-867057b144bb42c1b2e3320bb44d8299 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-12T21:19:11Z |
| publishDate | 2006-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-867057b144bb42c1b2e3320bb44d82992022-12-22T03:16:20ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582006-09-0129e13410.1371/journal.pcbi.0020134Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors.Xiaolin ChengHailong WangBarry GrantSteven M SineJ Andrew McCammonThe initial coupling between ligand binding and channel gating in the human alpha7 nicotinic acetylcholine receptor (nAChR) has been investigated with targeted molecular dynamics (TMD) simulation. During the simulation, eight residues at the tip of the C-loop in two alternating subunits were forced to move toward a ligand-bound conformation as captured in the crystallographic structure of acetylcholine binding protein (AChBP) in complex with carbamoylcholine. Comparison of apo- and ligand-bound AChBP structures shows only minor rearrangements distal from the ligand-binding site. In contrast, comparison of apo and TMD simulation structures of the nAChR reveals significant changes toward the bottom of the ligand-binding domain. These structural rearrangements are subsequently translated to the pore domain, leading to a partly open channel within 4 ns of TMD simulation. Furthermore, we confirmed that two highly conserved residue pairs, one located near the ligand-binding pocket (Lys145 and Tyr188), and the other located toward the bottom of the ligand-binding domain (Arg206 and Glu45), are likely to play important roles in coupling agonist binding to channel gating. Overall, our simulations suggest that gating movements of the alpha7 receptor may involve relatively small structural changes within the ligand-binding domain, implying that the gating transition is energy-efficient and can be easily modulated by agonist binding/unbinding.http://europepmc.org/articles/PMC1584325?pdf=render |
| spellingShingle | Xiaolin Cheng Hailong Wang Barry Grant Steven M Sine J Andrew McCammon Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors. PLoS Computational Biology |
| title | Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors. |
| title_full | Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors. |
| title_fullStr | Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors. |
| title_full_unstemmed | Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors. |
| title_short | Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors. |
| title_sort | targeted molecular dynamics study of c loop closure and channel gating in nicotinic receptors |
| url | http://europepmc.org/articles/PMC1584325?pdf=render |
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