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 language | English |
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Pages (from-to) | 126-143 |
Number of pages | 18 |
Journal | Journal of Structural Biology |
Volume | 150 |
Issue number | 2 |
DOIs | |
Publication status | Published - May 2005 |
MoE publication type | A1 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