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Originally published In Press as doi:10.1074/jbc.M102212200 on April 20, 2001

J. Biol. Chem., Vol. 276, Issue 28, 26148-26153, July 13, 2001
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Mechanism of Rhodopsin Activation as Examined with Ring-constrained Retinal Analogs and the Crystal Structure of the Ground State Protein*

Geeng-Fu JangDagger §, Vladimir KuksaDagger §, Stawomir Filipek, Franz Bartl||, Eglof Ritter||, Michael H. Gelb**Dagger Dagger , Klaus Peter Hofmann||, and Krzysztof PalczewskiDagger **§§¶¶

From the Departments of Dagger  Ophthalmology, §§ Pharmacology, ** Chemistry, and Dagger Dagger  Biochemistry, University of Washington, Seattle, Washington 98195, the  Department of Chemistry, University of Warsaw, 1 Pasteur Street, Warsaw PL-02093 Poland, and the || Institut für Medizinische Physik und Biophysik, Universitätsklinikum Charité, Humboldt Universität zu Berlin, Berlin D-10098, Germany

The guanine nucleotide-binding protein (G-protein)-coupled receptor superfamily (GPCR) is comprised of a large group of membrane proteins involved in a wide range of physiological signaling processes. The functional switch from a quiescent to an active conformation is at the heart of GPCR action. The GPCR rhodopsin has been studied extensively because of its key role in scotopic vision. The ground state chromophore, 11-cis-retinal, holds the transmembrane region of the protein in the inactive conformation. Light induces cis-trans isomerization and rhodopsin activation. Here we show that rhodopsin regenerated with a ring-constrained 11-cis-retinal analog undergoes photoisomerization; however, it remains marginally active because isomerization occurs without the chromophore-induced conformational change of the opsin moiety. Modeling the locked chromophore analogs in the active site of rhodopsin suggests that the beta -ionone ring rotates but is largely confined within the binding site of the natural 11-cis-retinal chromophore. This constraint is a result of the geometry of the stable 11-cis-locked configuration of the chromophore analogs. These results suggest that the native chromophore cis-trans isomerization is merely a mechanism for repositioning of the beta -ionone ring which ultimately leads to helix movements and determines receptor activation.

* This work was supported by National Institutes of Health Grant EY09339 (to K. P.), a grant from Research to Prevent Blindness, Inc. to the Department of Ophthalmology at the University of Washington, and grants from the Foundation Fighting Blindness, Inc., the Ruth and Milton Steinbach Fund, and the E. K. Bishop Foundation.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.

§ These authors contributed equally to this work.

¶¶ Senior Scientific Investigator of Research to Prevent Blindness, Inc. To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Box 356485, Seattle, WA 98195-6485. Tel.: 206-543-9074; Fax: 206-221-6784; E-mail: palczews@u.washington.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.