title: Model structures of alpha-2 adrenoceptors in complex with automatically docked antagonist ligands raise the possibility of interactions dissimilar from agonist ligands.
abstract: Antagonist binding to alpha-2 adrenoceptors (alpha2-ARs) is not well understood. Structural models were constructed for the three human alpha2-AR subtypes based on the bovine rhodopsin X-ray structure. Twelve antagonist ligands (including covalently binding phenoxybenzamine) were automatically docked to the models. A hallmark of agonist binding is the electrostatic interaction between a positive charge on the agonist and the negatively charged side chain of D3.32. For antagonist binding, ion-pair formation would require deviations of the models from the rhodopsin structural template, e.g., a rotation of TM3 to relocate D3.32 more centrally within the binding cavity, and/or creation of new space near TM2/TM7 such that antagonists would be shifted away from TM5. Thus, except for the quinazolines, antagonist ligands automatically docked to the model structures did not form ion-pairs with D3.32. This binding mode represents a valid alternative, whereby the positive charge on the antagonists is stabilized by cation-pi interactions with aromatic residues (e.g., F6.51) and antagonists interact with D3.32 via carboxylate-aromatic interactions. This binding mode is in good agreement with maps derived from a molecular interaction library that predicts favorable atomic contacts; similar interaction environments are seen for unrelated proteins in complex with ligands sharing similarities with the alpha2-AR antagonists.
authors.affiliation: Department of Biochemistry and Pharmacy, Abo Akademi University, Tykistökatu 6 A, FIN-20520 Turku, Finland.
authors.forename: Henri
authors.initials: H
authors.lastname: Xhaard
authors.forename: Tommi
authors.initials: T
authors.lastname: Nyrönen
authors.forename: Ville-Veikko
authors.initials: VV
authors.lastname: Rantanen
authors.forename: Jori O
authors.initials: JO
authors.lastname: Ruuskanen
authors.forename: Jonne
authors.initials: J
authors.lastname: Laurila
authors.forename: Tiina
authors.initials: T
authors.lastname: Salminen
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.forename: Mark S
authors.initials: MS
authors.lastname: Johnson
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010643:Phenoxybenzamine / Q000737:chemistry; D011485:Protein Binding; D011799:Quinazolines / Q000737:chemistry; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry; D055672:Static Electricity; D040681:Structural Homology, Protein; D015016:Yohimbine / Q000737:chemistry
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D008024:Ligands; D011799:Quinazolines; D018341:Receptors, Adrenergic, alpha-2; D010643:Phenoxybenzamine; D015016:Yohimbine; D012243:Rhodopsin