6DK0
Human sigma-1 receptor bound to NE-100
Summary for 6DK0
| Entry DOI | 10.2210/pdb6dk0/pdb |
| Descriptor | Sigma non-opioid intracellular receptor 1, N-{2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethyl}-N-propylpropan-1-amine, 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 | 81883.66 |
| 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 Cited by 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: 30291362DOI: 10.1038/s41594-018-0137-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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