Shifts in Backbone Conformation of Acetylcholinesterases upon Binding of Covalent Inhibitors, Reversible Ligands and Substrates
The influence of ligand binding to human, mouse and <i>Torpedo californica</i> acetylcholinesterase (EC 3.1.1.7; AChE) backbone structures is analyzed in a pairwise fashion by comparison with X-ray structures of unliganded AChEs. Both complexes with reversible ligands (substrates and inh...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Crystals |
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| Online Access: | https://www.mdpi.com/2073-4352/11/12/1557 |
| _version_ | 1797505599460605952 |
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| author | Zoran Radić |
| author_facet | Zoran Radić |
| author_sort | Zoran Radić |
| collection | DOAJ |
| description | The influence of ligand binding to human, mouse and <i>Torpedo californica</i> acetylcholinesterase (EC 3.1.1.7; AChE) backbone structures is analyzed in a pairwise fashion by comparison with X-ray structures of unliganded AChEs. Both complexes with reversible ligands (substrates and inhibitors) as well as covalently interacting ligands leading to the formation of covalent AChE conjugates of tetrahedral and of trigonal-planar geometries are considered. The acyl pocket loop (AP loop) in the AChE backbone is recognized as the conformationally most adaptive, but not necessarily sterically exclusive, structural element. Conformational changes of the centrally located AP loop coincide with shifts in C-terminal α-helical positions, revealing interacting components for a potential allosteric interaction within the AChE backbone. The stabilizing power of the aromatic choline binding site, with the potential to attract and pull fitting entities covalently tethered to the active Ser, is recognized. Consequently, the pull can promote catalytic reactions or relieve steric pressure within the impacted space of the AChE active center gorge. These dynamic properties of the AChE backbone inferred from the analysis of static X-ray structures contribute towards a better understanding of the molecular template important in the structure-based design of therapeutically active molecules, including AChE inhibitors as well as reactivators of conjugated, inactive AChE. |
| first_indexed | 2024-03-10T04:20:55Z |
| format | Article |
| id | doaj.art-66d6c284ef5349efbddf350c2115dcc5 |
| institution | Directory Open Access Journal |
| issn | 2073-4352 |
| language | English |
| last_indexed | 2024-03-10T04:20:55Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Crystals |
| spelling | doaj.art-66d6c284ef5349efbddf350c2115dcc52023-11-23T07:49:22ZengMDPI AGCrystals2073-43522021-12-011112155710.3390/cryst11121557Shifts in Backbone Conformation of Acetylcholinesterases upon Binding of Covalent Inhibitors, Reversible Ligands and SubstratesZoran Radić0Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093-0751, USAThe influence of ligand binding to human, mouse and <i>Torpedo californica</i> acetylcholinesterase (EC 3.1.1.7; AChE) backbone structures is analyzed in a pairwise fashion by comparison with X-ray structures of unliganded AChEs. Both complexes with reversible ligands (substrates and inhibitors) as well as covalently interacting ligands leading to the formation of covalent AChE conjugates of tetrahedral and of trigonal-planar geometries are considered. The acyl pocket loop (AP loop) in the AChE backbone is recognized as the conformationally most adaptive, but not necessarily sterically exclusive, structural element. Conformational changes of the centrally located AP loop coincide with shifts in C-terminal α-helical positions, revealing interacting components for a potential allosteric interaction within the AChE backbone. The stabilizing power of the aromatic choline binding site, with the potential to attract and pull fitting entities covalently tethered to the active Ser, is recognized. Consequently, the pull can promote catalytic reactions or relieve steric pressure within the impacted space of the AChE active center gorge. These dynamic properties of the AChE backbone inferred from the analysis of static X-ray structures contribute towards a better understanding of the molecular template important in the structure-based design of therapeutically active molecules, including AChE inhibitors as well as reactivators of conjugated, inactive AChE.https://www.mdpi.com/2073-4352/11/12/1557acetylcholinesteraseorganophosphatecarbamatebackbone conformationoxime reactivationoxime antidote |
| spellingShingle | Zoran Radić Shifts in Backbone Conformation of Acetylcholinesterases upon Binding of Covalent Inhibitors, Reversible Ligands and Substrates Crystals acetylcholinesterase organophosphate carbamate backbone conformation oxime reactivation oxime antidote |
| title | Shifts in Backbone Conformation of Acetylcholinesterases upon Binding of Covalent Inhibitors, Reversible Ligands and Substrates |
| title_full | Shifts in Backbone Conformation of Acetylcholinesterases upon Binding of Covalent Inhibitors, Reversible Ligands and Substrates |
| title_fullStr | Shifts in Backbone Conformation of Acetylcholinesterases upon Binding of Covalent Inhibitors, Reversible Ligands and Substrates |
| title_full_unstemmed | Shifts in Backbone Conformation of Acetylcholinesterases upon Binding of Covalent Inhibitors, Reversible Ligands and Substrates |
| title_short | Shifts in Backbone Conformation of Acetylcholinesterases upon Binding of Covalent Inhibitors, Reversible Ligands and Substrates |
| title_sort | shifts in backbone conformation of acetylcholinesterases upon binding of covalent inhibitors reversible ligands and substrates |
| topic | acetylcholinesterase organophosphate carbamate backbone conformation oxime reactivation oxime antidote |
| url | https://www.mdpi.com/2073-4352/11/12/1557 |
| work_keys_str_mv | AT zoranradic shiftsinbackboneconformationofacetylcholinesterasesuponbindingofcovalentinhibitorsreversibleligandsandsubstrates |