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6ME7

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

Summary for 6ME7
Entry DOI10.2210/pdb6me7/pdb
DescriptorSoluble cytochrome b562,Melatonin receptor type 1B,Rubredoxin, N-[2-(5-methoxy-2-phenyl-1H-indol-3-yl)ethyl]acetamide, ZINC ION, ... (4 entities in total)
Functional Keywordsgpcr, melatonin receptor type 1b (mt2), h208a mutation, membrane protein, 2-phenylmelatonin, xfel, lcp, bril, rubredoxin, circadian rhythm, jetlag, type 2 diabetes
Biological sourceEscherichia coli
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Total number of polymer chains2
Total formula weight103933.72
Authors
Primary citationJohansson, L.C.,Stauch, B.,McCorvy, J.D.,Han, G.W.,Patel, N.,Huang, X.P.,Batyuk, A.,Gati, C.,Slocum, S.T.,Li, C.,Grandner, J.M.,Hao, S.,Olsen, R.H.J.,Tribo, A.R.,Zaare, S.,Zhu, L.,Zatsepin, N.A.,Weierstall, U.,Yous, S.,Stevens, R.C.,Liu, W.,Roth, B.L.,Katritch, V.,Cherezov, V.
XFEL structures of the human MT2melatonin receptor reveal the basis of subtype selectivity.
Nature, 569:289-292, 2019
Cited by
PubMed Abstract: The human MT and MT melatonin receptors are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer, and MT has also been implicated in type 2 diabetes. Here we report X-ray free electron laser (XFEL) structures of the human MT receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H208A (superscripts represent the Ballesteros-Weinstein residue numbering nomenclature) and N86D, obtained in complex with 2-PMT. Comparison of the structures of MT with a published structure of MT reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [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 MT and MT, but in addition the MT 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 MT. 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.
PubMed: 31019305
DOI: 10.1038/s41586-019-1144-0
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (3.2 Å)
Structure validation

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