Subunit rotation models activation of serotonin 5-HT3AB receptors by agonists

  title={Subunit rotation models activation of serotonin 5-HT3AB receptors by agonists},
  author={G{\'a}bor Maksay and Mikl{\'o}s Simonyi and Zsolt Bik{\'a}di},
  journal={Journal of Computer-Aided Molecular Design},
SummaryThe N-terminal extracellular regions of heterooligomeric 3AB-type human 5-hydroxytryptamine receptors (5-HT 3ABR) were modelled based on the crystal structure of snail acetylcholine binding protein AChBP. Stepwise rotation of subunit A by 5° was performed between -10° and 15° to mimic agonist binding and receptor activation. Anticlockwise rotation reduced the size of the binding cavity in interface AB and reorganised the network of hydrogen bonds along the interface. AB subunit dimers… 

Allostery in pharmacology: thermodynamics, evolution and design.

  • G. Maksay
  • Biology, Chemistry
    Progress in biophysics and molecular biology
  • 2011

Allosteric modulation of 5-HT3 serotonin receptors.

Ligand-gated pentameric ion channels, from binding to gating.

  • G. Maksay
  • Biology, Chemistry
    Current molecular pharmacology
  • 2009
X-ray structures of molluscan acetylcholine-binding proteins and procaryotic proton-activated ion channels (ELIC and GLIC) enable us to model the ligand binding and activation mechanism of

Specific targeting of peripheral serotonin 5-HT(3) receptors. Synthesis, biological investigation, and structure-activity relationships.

Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5- HT(3)R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT( 3)R modulators endowed with a clear-cut pharmacological activity at the cardiac level.

Synthesis and Receptor Binding of New Thieno[2,3‐d]‐pyrimidines as Selective Ligands of 5‐HT3 Receptors

6‐ethyl‐4‐(4‐methyl‐1‐piperazinyl)‐2‐(methylthio)thieno[2,3‐d]pyrimidine 32 is the most potent ligand (Ki = 67 nM); it behaves as a competitive antagonist of the 5‐HT3 receptor function in the guinea pig colon.

MD-354: what is it good for?

Although devoid of antinociceptive actions following systemic administration alone, MD-354 markedly enhances the ant inocICEptive actions of clonidine in the mouse tail-flick assay without potentiating the sedative side effects ofClonidine.

Novel Analogs of m-Chlorophenylguanidine as 5-HT3 Receptor Ligands

Using halogenated analogs the study investigated their effect on binding to the 5-HT3 receptor and conformationally-constrained analogs (quinazolines) were shown to be a novel class of 5- HT3 receptor antagonists.



Binding Interactions of Antagonists with 5‐Hydroxytryptamine3A Receptor Models

A molecular explanation of the pharmacophore models of 5‐HT3R antagonists is offered and docking artifacts suggest some ambiguities in the binding loops A and C of the 5‐ HT3AR models.

Structural Features of the Ligand-binding Domain of the Serotonin 5HT3 Receptor*

Alanine-scanning mutagenesis analysis of the region centered on Trp-89 was carried out, and the ligand binding properties of the mutant receptors were determined, and it was suggested that this region of theligand-binding site of the 5HT3R (and by inference, other members of the lig and-gated ion channel family) is in a β-strand conformation.

Functional group interactions of a 5-HT3R antagonist

A tentative model of the lerisetron binding pocket of the 5-HT3ASR is proposed, according to which the N-benzyl group interacts in a weak interaction with R91 while the benzimidazole group interacts with W89.

Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine.

A cation-pi interaction between serotonin and Trp183 of the serotonin channel 5-HT(3A)R is identified for the first time, precisely locating the ligand-binding site of this receptor.

A structural model of agonist binding to the α3β4 neuronal nicotinic receptor

The present LBD model of the receptor in its free state provides a novel structural framework to interpret experimental observations and a useful template for future investigations to develop (α3)2(β4)3‐selective ligands.

Importance of phenylalanine 107 in agonist recognition by the 5-hydroxytryptamine(3A) receptor.

The effects of altering phenylalanine 107 (F107) of the 5-HT(3AL) subunit, obtained from NG108-15 cells, using site-directed mutagenesis are examined to suggest that F107 is an important determinant of agonist recognition at the5-HT (3) receptor.

Characterization of the Ligand-binding Site of the Serotonin 5-HT3 Receptor

To investigate the role of particular residues in ligand binding of the serotonin 5-HT3AS receptor, glutamate amino acid residues at three different positions in the extracellular N-terminal domain were substituted with aspartate and glutamine using site-directed mutagenesis.

Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors

The crystal structure of molluscan acetylcholine-binding protein (AChBP), a structural and functional homologue of the amino-terminal ligand-binding domain of an nAChR α-subunit, is presented and is relevant for the development of drugs against Alzheimer’s disease and nicotine addiction.

Identification of critical residues in loop E in the 5-HT3ASR binding site

Data provides support for the hypothesis that the putative E-loop region of the 5-HT3R is present in a loop structure, and supports the idea that this binding loop is comprised of a hairpin turn and may form a portion of the ligand-binding site in this ion channel family.