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J. Biol. Chem., Vol. 275, Issue 48, 37779-37788, December 1, 2000
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From the Previous work in the
The Forgotten Serine
A CRITICAL ROLE FOR Ser-2035.42 IN LIGAND
BINDING TO AND ACTIVATION OF THE 
2-ADRENERGIC
RECEPTOR*
§,
,§,,, and**§§
Center for Molecular Recognition and the
** Departments of Psychiatry and Pharmacology, Columbia University
College of Physicians and Surgeons and the New York
State Psychiatric Institute, New York, New York 10032 and the
¶ Department of Physiology and Biophysics, Mount Sinai School of
Medicine, New York, New York 10029
2-adrenergic receptor demonstrated critical
interactions between Ser-204 and Ser-207 in the fifth membrane-spanning segment and the meta-OH and para-OH,
respectively, of catecholamine agonists (Strader, C. D.,
Candelore, M. R., Hill, W. S., Sigal, I. S., and Dixon,
R. A. (1989) J. Biol. Chem. 264, 13572-13578). Using the substituted cysteine accessibility method in the
2-adrenergic receptor, we have found that in addition to
Ser-204 and Ser-207, Ser-203 is also accessible on the surface of the
binding-site crevice and is occluded by bound agonist. Mutation of
Ser-203 to Ala, Val, or Cys reduced the binding affinity and adenylyl cyclase-activating potency of agonists containing a
meta-OH, whereas their affinities and potencies were
largely preserved by mutation of Ser-203 to Thr, which maintained an OH
at this position. Thus both Ser-203 and Ser-204 appear to interact with
the meta-OH of catecholamines, perhaps through a bifurcated
H bond. Furthermore, the removal of the OH at position 203 led to a
significant loss of affinity of antagonists with nitrogen in their
heterocyclic ring structure. The greatest effect was seen with
pindolol, a partial agonist, suggesting that a H bond between the
heterocyclic ring and Ser-203 may play a role in partial agonism. In
contrast, the affinities of antagonists such as propranolol or
alprenolol, which have cyclic structures without H-bonding capability,
were unaltered after mutation of Ser-203.
*
This work was supported in part by National Institute of
Mental Health Grants MH57324 and MH54137, by the G. Harold and Leila Y. Mathers Charitable Trust, and by the Lebovitz Trust.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Novasite Pharmaceuticals, Inc., 3520 Dunhill
St., San Diego, CA 92121.
§§
To whom correspondence should be addressed: Center for Molecular
Recognition, Columbia University College of Physicians and Surgeons,
630 West 168th St., P&S 11-401, New York, NY 10032. Tel.: 212-305-7308;
Fax: 212-305-5594; E-mail: jaj2@columbia.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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