Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Nat Commun
2022 Mar 10;131:1267. doi: 10.1038/s41467-022-28946-w.
Show Gene links
Show Anatomy links
An open-like conformation of the sigma-1 receptor reveals its ligand entry pathway.
Meng F
,
Xiao Y
,
Ji Y
,
Sun Z
,
Zhou X
.
???displayArticle.abstract???
The sigma-1 receptor (σ1R) is a non-opioid transmembrane receptor which has been implicated in many diseases, including neurodegenerative disorders and cancer. After more than forty years of research, substantial progress has been made in understanding this unique receptor, yet the molecular mechanism of its ligand entry pathway remains uncertain. Published structures of human σ1R reveal its homotrimeric organization of a cupin-fold β-barrel body that contains the ligand binding site, a carboxy-terminal V-shaped two-helix bundle, and a single amino-terminal transmembrane helix, while simulation studies have suggested a ligand entry pathway that is generated by conformational rearrangements of the cupin-fold domain. Here, we present multiple crystal structures, including an open-like conformation, of σ1R from Xenopus laevis. Together with functional binding analysis our data suggest that access to the σ1R ligand binding site is likely achieved by protein conformational changes that involve the carboxy-terminal two-helix bundle, rather than structural changes in the cupin-fold domain.
Afonine,
Towards automated crystallographic structure refinement with phenix.refine.
2012, Pubmed
Afonine,
Towards automated crystallographic structure refinement with phenix.refine.
2012,
Pubmed
Aydar,
The sigma receptor as a ligand-regulated auxiliary potassium channel subunit.
2002,
Pubmed
,
Xenbase
Chen,
Release of hydrophobic molecules from polymer micelles into cell membranes revealed by Forster resonance energy transfer imaging.
2008,
Pubmed
Chu,
Biochemical Pharmacology of the Sigma-1 Receptor.
2016,
Pubmed
Davis,
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids.
2007,
Pubmed
Dunwell,
Cupins: the most functionally diverse protein superfamily?
2004,
Pubmed
Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed
Gregianin,
Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling.
2016,
Pubmed
Hanner,
Purification, molecular cloning, and expression of the mammalian sigma1-binding site.
1996,
Pubmed
Hayashi,
Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival.
2007,
Pubmed
Ho,
HOLLOW: generating accurate representations of channel and interior surfaces in molecular structures.
2008,
Pubmed
Hong,
Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons.
2015,
Pubmed
Kabsch,
XDS.
2010,
Pubmed
Kim,
Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding.
2010,
Pubmed
Kourrich,
Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine.
2013,
Pubmed
Kruse,
Structural Insights into Sigma1 Function.
2017,
Pubmed
Martin,
The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog.
1976,
Pubmed
McCoy,
Phaser crystallographic software.
2007,
Pubmed
Moreno,
Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects.
2014,
Pubmed
Navarro,
Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine.
2010,
Pubmed
Ossa,
A Review of the Human Sigma-1 Receptor Structure.
2017,
Pubmed
Rossino,
New Insights into the Opening of the Occluded Ligand-Binding Pocket of Sigma1 Receptor: Binding of a Novel Bivalent RC-33 Derivative.
2020,
Pubmed
Rousseaux,
Sigma receptors [σRs]: biology in normal and diseased states.
2016,
Pubmed
Schmidt,
Crystal structure of the human σ1 receptor.
2016,
Pubmed
Schmidt,
Structural basis for σ1 receptor ligand recognition.
2018,
Pubmed
Schneider,
NIH Image to ImageJ: 25 years of image analysis.
2012,
Pubmed
Su,
The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems.
2016,
Pubmed
Vilner,
Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines.
1995,
Pubmed
Vonrhein,
Data processing and analysis with the autoPROC toolbox.
2011,
Pubmed
Winn,
Overview of the CCP4 suite and current developments.
2011,
Pubmed
Wong,
Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases.
2016,
Pubmed
Yano,
Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays.
2018,
Pubmed
Zhou,
Structural basis of the alternating-access mechanism in a bile acid transporter.
2014,
Pubmed
