6dk0 | pdb_00006dk0
Human sigma-1 receptor bound to NE-100
Structural highlights
DiseaseSGMR1_HUMAN Juvenile amyotrophic lateral sclerosis. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionSGMR1_HUMAN Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration (PubMed:16472803, PubMed:9341151). Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria (By similarity).[UniProtKB:O55242][1] [2] Publication Abstract from PubMedThe sigma1 receptor is a poorly understood membrane protein expressed throughout the human body. Ligands targeting the sigma1 receptor are in clinical trials for treatment of Alzheimer's disease, ischemic stroke, and neuropathic pain. However, relatively little is known regarding the sigma1 receptor's molecular function. Here, we present crystal structures of human sigma1 receptor bound to the antagonists haloperidol and NE-100, and 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 identify agonist-induced structural rearrangements in the receptor. Additionally, we show that ligand binding to sigma1 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 sigma1 agonism. Structural basis for sigma1 receptor ligand recognition.,Schmidt HR, Betz RM, Dror RO, Kruse AC Nat Struct Mol Biol. 2018 Oct;25(10):981-987. doi: 10.1038/s41594-018-0137-2., Epub 2018 Oct 5. PMID:30291362[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
