The extracellular subunit interface of the 5-HT3 receptors: a computational alanine scanning mutagenesis study

• Type: Article in International Scientific Journal
• Date: 2012

Authors

Francesca De Rienzo (Author) Other; Armenio Moura M Barbosa (Author) Other; Marta A S Perez (Author) Other; Pedro A Fernandes (Author) FCUP; Maria J Ramos (Author) FCUP; Maria Cristina Menziani (Author) Other

Journal

Title: Journal of Biomolecular Structure and Dynamics

Vol. 30

Pages: 280-298

ISSN: 0739-1102

Publisher: Taylor & Francis

Indexing

ISI Web of Knowledge - 6 Citations

Scopus - 5 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-002-G4V

DOI: 10.1080/07391102.2012.680029

Abstract (EN): The functional serotonin 5-HT type-3 (5-HT3) receptor, the target of many neuroactive drugs, is known to be a pseudo-symmetric pentamer made either of five identical subunits A (homomeric 5-HT3A-R) or of subunits A and B (heteromeric 5-HT3A/B-R) in a still debated arrangement. The serotonin binding site is located in the extracellular region, at the interface between two monomers, called the principal and the complementary subunits. The results of molecular dynamics simulations and computational alanine scanning mutagenesis studies applied here to the homomeric human 5-HT3A-R disclose an aromatic "hot" cluster in the centre of the interface formed by residues W178 (principal subunit), Y68, Y83, W85 and Y148 (complementary subunit). Moreover, investigation of the coupling of agonist/antagonist binding to channel activation/inactivation points out the presence of two putative functional pathways at the subunit interface: W116-H180-L179-W178-E124-F125 (principal subunit) and Y136-Y138-Y148-W85-(P150) (complementary subunit), where W178 and Y148 appear to be critical residues for the binding/activation mechanism. Finally, direct comparison of the main features shown by the AA interface in the human 5-HT3A-R with those of the BB interface in the homopentameric human 5-HT3B-R provides interesting clues about the possible reasons that cause the 5-HT3B-R not to be functional.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 19