Conformational selection of vasopressin upon V1a receptor binding
The neuropeptide vasopressin (VP) and its three G protein-coupled receptors (V1aR, V1bR and V2R) are of high interest in a wide array of drug discovery programs. V1aR is of particular importance due to its cardiovascular functions and diverse roles in the central nervous system. The structure–activi...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037021004463 |
| _version_ | 1819320358811992064 |
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| author | Kateryna Che Markus Muttenthaler Dennis Kurzbach |
| author_facet | Kateryna Che Markus Muttenthaler Dennis Kurzbach |
| author_sort | Kateryna Che |
| collection | DOAJ |
| description | The neuropeptide vasopressin (VP) and its three G protein-coupled receptors (V1aR, V1bR and V2R) are of high interest in a wide array of drug discovery programs. V1aR is of particular importance due to its cardiovascular functions and diverse roles in the central nervous system. The structure–activity relationships underpinning ligand-receptor interactions remain however largely unclear, hindering rational drug design. This is not least due to the high structural flexibility of VP in its free as well as receptor-bound states. In this work, we developed a novel approach to reveal features of conformational selectivity upon VP-V1aR complex formation. We employed virtual screening strategies to probe VP’s conformational space for transiently adopted structures that favor binding to V1aR. To this end, we dissected the VP conformational space into three sub-ensembles, each containing distinct structural sets for VP’s three-residue C-terminal tail. We validated the computational results with experimental nuclear magnetic resonance (NMR) data and docked each sub-ensemble to V1aR. We observed that the conformation of VP’s three-residue tail significantly modulated the complex dissociation constants. Solvent-exposed and proline trans-configured VP tail conformations bound to the receptor with three-fold enhanced affinities compared to compacted or cis-configured conformations. The solvent-exposed and more flexible structures facilitated unique interaction patterns between VP and V1aR transmembrane helices 3, 4, and 6 which led to high binding energies. The presented “virtual conformational space screening” approach, integrated with NMR spectroscopy, thus enabled identification and characterization of a conformational selection-type complex formation mechanism that confers novel perspectives on targeting the VP-V1aR interactions at the level of the encounter complex – an aspect that opens novel research avenues for understanding the functionality of the evolutionary selected conformational properties of VP, as well as guidance for ligand design strategies to provide more potent and selective VP analogues. |
| first_indexed | 2024-12-24T11:18:19Z |
| format | Article |
| id | doaj.art-0edf8daa77ee4c479910bae4c1543cc2 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-12-24T11:18:19Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-0edf8daa77ee4c479910bae4c1543cc22022-12-21T16:58:19ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011958265833Conformational selection of vasopressin upon V1a receptor bindingKateryna Che0Markus Muttenthaler1Dennis Kurzbach2University Vienna, Faculty of Chemistry, Institute of Biological Chemistry, Währinger Str. 38, A-1090 Vienna, AustriaUniversity Vienna, Faculty of Chemistry, Institute of Biological Chemistry, Währinger Str. 38, A-1090 Vienna, Austria; The University of Queensland, Institute for Molecular Bioscience, 306 Carmody Rd, 4072 St Lucia, Brisbane, Queensland, AustraliaUniversity Vienna, Faculty of Chemistry, Institute of Biological Chemistry, Währinger Str. 38, A-1090 Vienna, Austria; Corresponding author.The neuropeptide vasopressin (VP) and its three G protein-coupled receptors (V1aR, V1bR and V2R) are of high interest in a wide array of drug discovery programs. V1aR is of particular importance due to its cardiovascular functions and diverse roles in the central nervous system. The structure–activity relationships underpinning ligand-receptor interactions remain however largely unclear, hindering rational drug design. This is not least due to the high structural flexibility of VP in its free as well as receptor-bound states. In this work, we developed a novel approach to reveal features of conformational selectivity upon VP-V1aR complex formation. We employed virtual screening strategies to probe VP’s conformational space for transiently adopted structures that favor binding to V1aR. To this end, we dissected the VP conformational space into three sub-ensembles, each containing distinct structural sets for VP’s three-residue C-terminal tail. We validated the computational results with experimental nuclear magnetic resonance (NMR) data and docked each sub-ensemble to V1aR. We observed that the conformation of VP’s three-residue tail significantly modulated the complex dissociation constants. Solvent-exposed and proline trans-configured VP tail conformations bound to the receptor with three-fold enhanced affinities compared to compacted or cis-configured conformations. The solvent-exposed and more flexible structures facilitated unique interaction patterns between VP and V1aR transmembrane helices 3, 4, and 6 which led to high binding energies. The presented “virtual conformational space screening” approach, integrated with NMR spectroscopy, thus enabled identification and characterization of a conformational selection-type complex formation mechanism that confers novel perspectives on targeting the VP-V1aR interactions at the level of the encounter complex – an aspect that opens novel research avenues for understanding the functionality of the evolutionary selected conformational properties of VP, as well as guidance for ligand design strategies to provide more potent and selective VP analogues.http://www.sciencedirect.com/science/article/pii/S2001037021004463Molecular recognitionConformational selectionMolecular dynamic simulationsIn silico dockingNMR spectropscopyVasopressin |
| spellingShingle | Kateryna Che Markus Muttenthaler Dennis Kurzbach Conformational selection of vasopressin upon V1a receptor binding Computational and Structural Biotechnology Journal Molecular recognition Conformational selection Molecular dynamic simulations In silico docking NMR spectropscopy Vasopressin |
| title | Conformational selection of vasopressin upon V1a receptor binding |
| title_full | Conformational selection of vasopressin upon V1a receptor binding |
| title_fullStr | Conformational selection of vasopressin upon V1a receptor binding |
| title_full_unstemmed | Conformational selection of vasopressin upon V1a receptor binding |
| title_short | Conformational selection of vasopressin upon V1a receptor binding |
| title_sort | conformational selection of vasopressin upon v1a receptor binding |
| topic | Molecular recognition Conformational selection Molecular dynamic simulations In silico docking NMR spectropscopy Vasopressin |
| url | http://www.sciencedirect.com/science/article/pii/S2001037021004463 |
| work_keys_str_mv | AT katerynache conformationalselectionofvasopressinuponv1areceptorbinding AT markusmuttenthaler conformationalselectionofvasopressinuponv1areceptorbinding AT denniskurzbach conformationalselectionofvasopressinuponv1areceptorbinding |