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2 Adrenergic
Receptor Alters the Orientation of Its Sixth Membrane-spanning
Segment
(Received for publication, April 30, 1997, and in revised form, May 30, 1997)
§¶
,
,
and
From the The binding site of the Center for Molecular Recognition and the
§ Departments of Psychiatry and Pharmacology, Columbia
University College of Physicians & Surgeons, New York, New York 10032 and the ¶ New York State Psychiatric Institute, New York, New York
10032
2
adrenergic receptor, like that of other homologous G-protein-coupled
receptors, is contained within a water-accessible crevice formed among
its seven membrane-spanning segments. Methanethiosulfonate
ethylammonium (MTSEA), a charged, hydrophilic, lipophobic,
sulfhydryl-specific reagent, had no effect on the binding of agonist or
antagonist to wild-type 2 receptor expressed in HEK 293 cells. This suggested that no endogenous cysteines are accessible in
the binding site crevice. In contrast, in a constitutively active
2 receptor, MTSEA significantly inhibited antagonist
binding, and isoproterenol slowed the rate of reaction of MTSEA. This
implies that at least one endogenous cysteine becomes accessible in the
binding site crevice of the constitutively active 2
receptor. Cys-285, in the sixth membrane-spanning segment, is
responsible for the inhibitory effect of MTSEA on ligand binding to the
constitutively active mutant. The acquired accessibility of Cys-285 in
the constitutively active mutant may result from a rotation and/or
tilting of the sixth membrane-spanning segment associated with
activation of the receptor. This rearrangement could bring Cys-285 to
the margin of the binding site crevice where it becomes accessible to
MTSEA.
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