Model structures of α-2 adrenoceptors in complex with automatically docked antagonist ligands raise the possibility of interactions dissimilar from agonist ligands

Henri Xhaard, Tommi Nyrönen, Ville-Veikko Rantanen, Jori O. Ruuskanen, Jonne Laurila, Tiina Salminen, Mika Scheinin, Mark S. Johnson

Research output: Contribution to journalArticleScientificpeer-review

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)126-143
Number of pages18
JournalJournal of Structural Biology
Volume150
Issue number2
DOIs
Publication statusPublished - May 2005
MoE publication typeA1 Journal article-refereed

Keywords

  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-2 Receptor Antagonists
  • Computer Simulation
  • Humans
  • Ligands
  • Models, Molecular
  • Phenoxybenzamine/chemistry
  • Protein Binding
  • Quinazolines/chemistry
  • Receptors, Adrenergic, alpha-2/chemistry
  • Rhodopsin/chemistry
  • Static Electricity
  • Structural Homology, Protein
  • Yohimbine/chemistry

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