Structural basis for sigma-1 receptor ligand recognition

Abstract

The {sigma}1 receptor is a poorly understood integral membrane protein expressed in most cells and tissues in the human body. It has been shown to modulate the activity of other membrane proteins such as ion channels and G protein-coupled receptors1-4, and ligands targeting the {sigma}1 receptor are currently in clinical trials for treatment of Alzheimers disease5, ischemic stroke6, and neuropathic pain7. Despite its importance, relatively little is known regarding {sigma}1 receptor function at the molecular level. Here, we present crystal structures of the human {sigma}1 receptor bound to the classical antagonists haloperidol and NE-100, as well as the agonist (+)-pentazocine, at crystallographic resolutions of 3.1 [A], 2.9 [A], and 3.1 [A] respectively. These structures reveal a unique binding pose for the agonist. The structures and accompanying molecular dynamics (MD) simulations demonstrate that the agonist induces subtle structural rearrangements in the receptor. In addition, we show that ligand binding and dissociation from {sigma}1 is a multistep process, with extraordinarily slow kinetics limited by receptor conformational change. We use MD simulations to reconstruct a ligand binding pathway that requires two major conformational changes. Taken together, these data provide a framework for understanding the molecular basis for agonist action at {sigma}1.