Structure of the human σ1 receptor
Andrew Kruse group (Harvard University)
Andrew Kruse and his group determined the structure of
the enigmatic human σ1 receptor. The transmembrane
receptor is located in the endoplasmic reticulum (ER) membrane and is
implicated in a variety of neurological disorders including depression,
drug addiction, and neuropathic pain. It has also been linked to
amyotrophic lateral sclerosis (ALS). Although first identified about
50 years ago by its ability to bind radiolabelled opioids,
σ1 is not considered a true opioid receptor, and it is
not a GPCR. Until now, the structure has been elusive and basic
questions, such as the number of transmembrane domains, remained
unanswered. The Kruse lab grew crystals in the lipid cubic phase
(LCP), and used data from GM/[email protected] beamlines 23ID-D and 23ID-B and
from NE CAT to determine the structure. The trimeric receptor has a
triangular architecture with a single transmembrane helix in each
protomer. An extensive hydrophobic surface on the C-terminal extrinsic
domain presumably associates with the cytosolic surface of the ER
membrane. The extrinsic domain has a cupin-like β-barrel fold
with a large, hydrophobic ligand-binding cavity. The ligand-binding
cavity shows remarkable plasticity in ligand recognition, as seen in
complexes with two dissimilar ligands, which bind in similar positions.
In addition, the structure showed the structural basis for receptor
destabilization resulting from an ALS-associated mutation. Knowledge of
the σ1 receptor structure opens the door to detailed
investigation of its role in both normal and pathophysiological
conditions.
 | Figure:
Structure of the trimeric human σ1 receptor, showing
the N-terminal transmembrane helix and the C-terminal ligand-binding
domain of the blue, orange and green monomers. |
Citation: Schmidt, H.R., Zheng, S., Gurpinar, E.,
Koehl, A., Manglik, A., Kruse, A.C. (2016) Crystal structure of
the human σ1 receptor, Nature, 532, 527-530.
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