Antagonist conformations within the β2-adrenergic receptor ligand binding pocket

Gregory H. Hockerman, Mark E. Girvin, Craig C. Malbon, Arnold E. Ruoho

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The interactions between β-adrenergic receptor (βAR) antagonists and the β2AR were studied with the use of photoaffinity labels. A proteolytic map of the receptor was made and confirmed through amino-terminal amino acid sequencing by locating sites of derivatization. [125I]lodoazidothiophenylalprenolol (IAPTA) is a photoaffinity derivative of the βAR antagonist alprenolol with a photoactivatable group on the aryloxy end of the molecule. IAPTA exclusively derivatizes a peptide consisting of transmembrane domains (TMs) 6 and 7 of the hamster lung β2AR, supporting the contention that TMs 6 and 7 interact with the aryloxy portion of the βAR antagonist pharmacophore. The βAR antagonist photoaffinity labels [125I]iodoazidobenzylpindolol (IABP), [125I]iodoazidophenyl CGP- 12177A (IAPCGP), and [125I]iodocyanopindololdiazarene (ICYPdz) are similar in that their photoactive moieties are attached to the amino end of the antagonist pharmacophore. IABP derivatized TMs 5-7 and a peptide containing TM 1 to approximately equal extents. IAPCGP derivatized TMs 6 and 7 >> TM 5 = TM 4 = TMs 2 and 3 = TM 1. ICYPdz derivatized TM 1 >> TMs 6 and 7 > TM 4. We conclude that the aryloxy end of the βAR antagonist pharmacophore is highly constrained within TMs 6 and 7, whereas the amino terminus is much less constrained and able to assume multiple conformations. Molecular dynamics simulations predict that IABP, IAPCGP, and ICYPdz favor a folded conformation, with both ends close together. Derivatization of TMs 6 and 7 by IABP, IAPCGP, and ICYPdz suggests the folded conformation of these compounds in the ligand binding pocket.

Original languageEnglish (US)
Pages (from-to)1021-1032
Number of pages12
JournalMolecular Pharmacology
Volume49
Issue number6
StatePublished - Jun 1996
Externally publishedYes

Fingerprint

Adrenergic Antagonists
Adrenergic Receptors
Ligands
Photoaffinity Labels
Alprenolol
Peptides
Protein Sequence Analysis
Molecular Dynamics Simulation
Cricetinae
Lung
CGP 12177
1-(indol-4-yloxy)-3-(1-(4-azido-3-iodophenyl)-2-isobutylamine)-2-propanol

ASJC Scopus subject areas

  • Pharmacology

Cite this

Hockerman, G. H., Girvin, M. E., Malbon, C. C., & Ruoho, A. E. (1996). Antagonist conformations within the β2-adrenergic receptor ligand binding pocket. Molecular Pharmacology, 49(6), 1021-1032.

Antagonist conformations within the β2-adrenergic receptor ligand binding pocket. / Hockerman, Gregory H.; Girvin, Mark E.; Malbon, Craig C.; Ruoho, Arnold E.

In: Molecular Pharmacology, Vol. 49, No. 6, 06.1996, p. 1021-1032.

Research output: Contribution to journalArticle

Hockerman, GH, Girvin, ME, Malbon, CC & Ruoho, AE 1996, 'Antagonist conformations within the β2-adrenergic receptor ligand binding pocket', Molecular Pharmacology, vol. 49, no. 6, pp. 1021-1032.
Hockerman GH, Girvin ME, Malbon CC, Ruoho AE. Antagonist conformations within the β2-adrenergic receptor ligand binding pocket. Molecular Pharmacology. 1996 Jun;49(6):1021-1032.
Hockerman, Gregory H. ; Girvin, Mark E. ; Malbon, Craig C. ; Ruoho, Arnold E. / Antagonist conformations within the β2-adrenergic receptor ligand binding pocket. In: Molecular Pharmacology. 1996 ; Vol. 49, No. 6. pp. 1021-1032.
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