Structural basis for σ1 receptor ligand recognition.
Hayden R SchmidtRobin M BetzRon O DrorAndrew C KrusePublished in: Nature structural & molecular biology (2018)
The σ1 receptor is a poorly understood membrane protein expressed throughout the human body. Ligands targeting the σ1 receptor are in clinical trials for treatment of Alzheimer's disease, ischemic stroke, and neuropathic pain. However, relatively little is known regarding the σ1 receptor's molecular function. Here, we present crystal structures of human σ1 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 σ1 is a multistep process that is rate limited by receptor conformational change. We used MD simulations to reconstruct a ligand binding pathway involving two major conformational changes. These data provide a framework for understanding the molecular basis for σ1 agonism.
Keyphrases
- molecular dynamics
- clinical trial
- neuropathic pain
- endothelial cells
- binding protein
- density functional theory
- spinal cord
- spinal cord injury
- high resolution
- randomized controlled trial
- single molecule
- gene expression
- molecular dynamics simulations
- structural basis
- cognitive decline
- electronic health record
- genome wide
- drug delivery
- big data
- open label
- diabetic rats
- replacement therapy