title: Structural determinants of subtype selectivity and functional activity of angiotensin II receptors.
abstract: Agonists of the angiotensin II receptor type 2 (AT2), a G-protein coupled receptor, promote tissue protective effects in cardiovascular and renal diseases, while antagonists reduce neuropathic pain. We here report detailed molecular models that explain the AT2 receptor selectivity of our recent series of non-peptide ligands. In addition, minor structural changes of these ligands that provoke different functional activity are rationalized at a molecular level, and related to the selectivity for the different receptor conformations. These findings should pave the way to structure based drug discovery of AT2 receptor ligands.
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sallander
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, Biomedical Center, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Wallinder
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, Biomedical Center, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Åqvist
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden. Electronic address: hugo.gutierrez@icm.uu.se.
authors.forename: Hugo
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
mesh_terms: D000595:Amino Acid Sequence; D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2
keywords: Angiotensin receptors; Conformational selection; Homology modeling; Ligand interaction; Molecular docking