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Summary: Conserved Binding Mode of Human 2 Adrenergic Receptor Inverse Agonists
and Antagonist Revealed by X-ray Crystallography
Daniel Wacker,,
Gustavo Fenalti,,
Monica A. Brown,,
Vsevolod Katritch,§
Ruben Abagyan,§
Vadim Cherezov,
and Raymond C. Stevens*,
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037 and UniVersity of
California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, California 92093
Received June 11, 2010; E-mail: stevens@scripps.edu
Abstract: G protein-coupled receptors (GPCRs) represent a large
fraction of current pharmaceutical targets, and of the GPCRs, the
2 adrenergic receptor ( 2AR) is one of the most extensively
studied. Previously, the X-ray crystal structure of 2AR has been
determined in complex with two partial inverse agonists, but the
global impact of additional ligands on the structure or local impacts
on the binding site are not well-understood. To assess the extent
of such ligand-induced conformational differences, we determined
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