alexa Phenoxybenzamine binding reveals the helical orientation of the third transmembrane domain of adrenergic receptors.
Bioinformatics & Systems Biology

Bioinformatics & Systems Biology

Journal of Computer Science & Systems Biology

Author(s): Frang H, Cockcroft V, Karskela T, Scheinin M, Marjamki A

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Abstract Phenoxybenzamine (PB), a classical alpha-adrenergic antagonist, binds irreversibly to the alpha-adrenergic receptors (ARs). Amino acid sequence alignments and the predicted helical arrangement of the seven transmembrane (TM) domains suggested an accessible cysteine residue in transmembrane 3 of the alpha(2)-ARs, in position C(3.36) (in subtypes A, B, and C corresponding to amino acid residue numbers 117/96/135, respectively), as a possible site for the PB interaction. Irreversible binding of PB to recombinant human alpha(2)-ARs (90 nm, 30 min) reduced the ligand binding capacity of alpha(2A)-, alpha(2B)-, and alpha(2C)-AR by 81, 96, and 77\%. When the TM3 cysteine, Cys(117), of alpha(2A)-AR was mutated to valine (alpha(2A)-C117V), the receptor became resistant to PB (inactivation, 10\%). The beta(2)-AR contains a valine in this position (V(3.36); position number 117) and a cysteine in the preceding position (Cys(116)) and was not inactivated by PB (10 microm, 30 min) (inactivation 26\%). The helical orientation of TM3 was tested by exchanging the amino acids at positions 116 and 117 of the alpha(2A)-AR and beta(2)-AR. The alpha(2A)-F116C/C117V mutant was resistant to PB (inactivation, 7\%), whereas beta(2)-V117C was irreversibly inactivated (inactivation, 93\%), confirming that position 3.36 is exposed to receptor ligands, and position 3.35 is not exposed in the binding pocket. This article was published in J Biol Chem and referenced in Journal of Computer Science & Systems Biology

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