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Molecular Pharmacology

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Abstract

Antagonist conformations with the beta(2)-adrenergic receptor ligand binding pocket.

G H Hockerman, M E Girvin, C C Malbon and A E Ruoho
Molecular Pharmacology June 1996, 49 (6) 1021-1032;
G H Hockerman
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M E Girvin
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C C Malbon
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A E Ruoho
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Abstract

The interactions between beta-adrenergic receptor (beta AR) antagonists and the beta(2)AR 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]Iodoazidothiophenylalprenolol (IAPTA) is a photoaffinity derivative of the beta AR 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 beta(2)AR, supporting the contention that TMs 6 and 7 interact with the aryloxy portion of the beta AR antagonist pharmacophore. The beta AR 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 beta AR 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.

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Molecular Pharmacology
Vol. 49, Issue 6
1 Jun 1996
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Abstract

Antagonist conformations with the beta(2)-adrenergic receptor ligand binding pocket.

G H Hockerman, M E Girvin, C C Malbon and A E Ruoho
Molecular Pharmacology June 1, 1996, 49 (6) 1021-1032;

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Abstract

Antagonist conformations with the beta(2)-adrenergic receptor ligand binding pocket.

G H Hockerman, M E Girvin, C C Malbon and A E Ruoho
Molecular Pharmacology June 1, 1996, 49 (6) 1021-1032;
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