NDLI: Approaching the 5-HT$_{3}$ receptor heterogeneity by computational studies of the transmembrane and intracellular domains

Content Provider	Springer Nature Link
Author	Cadia, Marta Rienzo, Francesca Menziani, Maria Cristina
Copyright Year	2013
Abstract	5-hydroxytryptamine type-3 receptor (5-HT$_{3}$), an important target of many neuroactive drugs, is a cation selective transmembrane pentamer whose functional stoichiometries and subunit arrangements are still debated, due to the extreme complexity of the system. The three dimensional structure of the 5-HT$_{3}$R subunits has not been solved so far. Moreover, most of the available structural and functional data is related to the extracellular ligand-binding domain, whereas the transmembrane and the intracellular receptor domains are far less characterised, although they are crucial for receptor function. Here, for the first time, 3D homology models of the transmembrane and the intracellular receptor domains of all the known human 5-HT$_{3}$ subunits have been built and assembled into homopentameric (5-HT$_{3A}$R, 5-HT$_{3B}$R, 5-HT$_{3C}$R, 5-HT$_{3D}$R and 5-HT$_{3E}$R) and heteropentameric receptors (5-HT$_{3AB}$, 5-HT$_{3AC}$, 5-HT$_{3AD}$ and 5-HT$_{3AE}$), on the basis of the known three-dimensional structures of the nicotinic-acetylcholine receptor and of the ligand gated channel from Erwinia chrysanthemi. The comparative analyses of sequences, modelled structures, and computed electrostatic properties of the single subunits and of the assembled pentamers shed new light both on the stoichiometric composition and on the physicochemical requirements of the functional receptors. In particular, it emerges that a favourable environment for the crossing of the pore at the transmembrane and intracellular C terminus domain levels by Ca$^{2+}$ ions is granted by the maximum presence of two B subunits in the 5-HT$_{3}$ pentamer.
Starting Page	491
Ending Page	509
Page Count	19
File Format	PDF
ISSN	0920654X
Journal	Journal of Computer-Aided Molecular Design
Volume Number	27
Issue Number	6
e-ISSN	15734951
Language	English
Publisher	Springer Netherlands
Publisher Date	2013-06-16
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Homology modelling 5-HT$_{3}$ receptors Electrostatic potential map Energy profile Physical Chemistry Computer Applications in Chemistry Animal Anatomy / Morphology / Histology
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Physical and Theoretical Chemistry Computer Science Applications

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