6me7 | pdb_00006me7

XFEL crystal structure of human melatonin receptor MT2 (H208A) in complex with 2-phenylmelatonin

spinqualitylabelsall models 6me7, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6me7 is a 2 chain structure with sequence from Clostridium pasteurianum, Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.2Å Ligands: JEY, OLC, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function C562_ECOLX Electron-transport protein of unknown function.RUBR_CLOPA Rubredoxin is a small nonheme, iron protein lacking acid-labile sulfide. Its single Fe, chelated to 4 Cys, functions as an electron acceptor and may also stabilize the conformation of the molecule.MTR1B_HUMAN High affinity receptor for melatonin. Likely to mediate the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity. Publication Abstract from PubMed The human MT1 and MT2 melatonin receptors(1,2) are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns(3). Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer(3), and MT2 has also been implicated in type 2 diabetes(4,5). Here we report X-ray free electron laser (XFEL) structures of the human MT2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon(6) at resolutions of 2.8 A and 3.3 A, respectively, along with two structures of function-related mutants: H208(5.46)A (superscripts represent the Ballesteros-Weinstein residue numbering nomenclature(7)) and N86(2.50)D, obtained in complex with 2-PMT. Comparison of the structures of MT2 with a published structure(8) of MT1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [(3)H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT1 and MT2, but in addition the MT2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT2. Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents. XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity.,Johansson LC, Stauch B, McCorvy JD, Han GW, Patel N, Huang XP, Batyuk A, Gati C, Slocum ST, Li C, Grandner JM, Hao S, Olsen RHJ, Tribo AR, Zaare S, Zhu L, Zatsepin NA, Weierstall U, Yous S, Stevens RC, Liu W, Roth BL, Katritch V, Cherezov V Nature. 2019 May;569(7755):289-292. doi: 10.1038/s41586-019-1144-0. Epub 2019 Apr, 24. PMID:31019305 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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