6DK1

Human sigma-1 receptor bound to (+)-pentazocine

Summary for 6DK1

• Entry DOI: 10.2210/pdb6dk1/pdb
• Descriptor: Sigma non-opioid intracellular receptor 1, (2S,6S,11S)-6,11-dimethyl-3-(3-methylbut-2-en-1-yl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-ol, SULFATE ION, ... (6 entities in total)
• Functional Keywords: membrane protein, antagonist bound, receptor, sigma-1 receptor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 82835.11

Authors

Schmidt, H.R.,Kruse, A.C. (deposition date: 2018-05-28, release date: 2018-10-17, Last modification date: 2023-10-11)

Primary citation

Schmidt, H.R.,Betz, R.M.,Dror, R.O.,Kruse, A.C.
Structural basis for sigma1receptor ligand recognition.
Nat. Struct. Mol. Biol., 25:981-987, 2018

PubMed Abstract: The σ receptor is a poorly understood membrane protein expressed throughout the human body. Ligands targeting the σ receptor are in clinical trials for treatment of Alzheimer's disease, ischemic stroke, and neuropathic pain. However, relatively little is known regarding the σ receptor's molecular function. Here, we present crystal structures of human σ 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 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 σ agonism.

PubMed: 30291362
DOI: 10.1038/s41594-018-0137-2

Experimental method

X-RAY DIFFRACTION (3.12 Å)