Structural Perspectives on Sigma-1 Receptor Function.
The sigma-1 receptor is an enigmatic ER-resident transmembrane protein linked to a variety of human diseases. Although the receptor was first cloned 20 years ago, the molecular structure of the protein and the mechanistic basis for its interaction with drug-like small molecules have remained unclear until recently. The determination of the first crystal structure of human sigma-1 offered the first detailed views of the sigma-1 architecture, and revealed an unusual overall fold with a single transmembrane helix in each protomer. The structure shows an overall trimeric receptor arrangement, and each protomer binds a single ligand molecule at the center of its carboxy-terminal domain. These results offer detailed molecular views of receptor structure, oligomerization, and ligand recognition, providing a framework for the next era of sigma-1 research.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
Assaf
A
Alon
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
Hayden
H
Schmidt
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
Sanduo
S
Zheng
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA. andrew_kruse@hms.harvard.edu.
Andrew C
AC
Kruse
D000818:Animals; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D017480:Receptors, sigma / Q000737:chemistry* / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D008024:Ligands; D021122:Protein Subunits; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
Crystallography; Lipidic cubic phase; Membrane protein; Sigma-1 receptor; Structural biology