title: Structural basis of ligand recognition in 5-HT3 receptors.
abstract: The 5-HT(3) receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT(3) receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation-π interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT(3) receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT(3) receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT(3) receptor.
authors.affiliation: Laboratory of Structural Neurobiology, KULeuven, Leuven, Belgium.
authors.forename: Divya
authors.initials: D
authors.lastname: Kesters
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Marijke
authors.initials: M
authors.lastname: Brams
authors.forename: René
authors.initials: R
authors.lastname: van Elk
authors.forename: Radovan
authors.initials: R
authors.lastname: Spurny
authors.forename: Matthis
authors.initials: M
authors.lastname: Geitmann
authors.forename: Jose M
authors.initials: JM
authors.lastname: Villalgordo
authors.forename: Albert
authors.initials: A
authors.lastname: Guskov
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
authors.forename: Sarah C R
authors.initials: SC
authors.lastname: Lummis
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Chris
authors.initials: C
authors.lastname: Ulens
mesh_terms: D000595:Amino Acid Sequence; D000932:Antiemetics / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D017829:Granisetron / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry* / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D012701:Serotonin / Q000031:analogs & derivatives* / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000378:metabolism; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D000932:Antiemetics; D017829:Granisetron; D008024:Ligands; D021122:Protein Subunits; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins; D012701:Serotonin; D017366:Serotonin Receptor Agonists