Structural basis for σ(1) receptor ligand recognition

The σ(1) receptor is a poorly understood membrane protein expressed throughout the human body. Ligands targeting the σ(1) receptor are in clinical trials for treatment of Alzheimer’s disease, ischemic stroke, and neuropathic pain. Despite this, relatively little is known regarding the σ(1) receptor’s molecular function. Here, we present crystal structures of human σ(1) receptor bound to the antagonists haloperidol and NE-100, and the agonist (+)-pentazocine, at crystallographic resolutions of 3.1 Å, 2.9 Å, and 3.1 Å respectively. These structures reveal a unique binding pose for the agonist. The structures and accompanying molecular dynamics (MD) simulations identify agonist-induced structural rearrangements in the receptor. Additionally, we show that ligand binding to σ(1) is a multistep process, rate-limited by receptor conformational change. We use MD simulations to reconstruct a ligand binding pathway involving two major conformational changes. These data provide a framework for understanding the molecular basis for σ(1) agonism.