Interactions of granisetron with an agonist-free 5-HT3A receptor model

Prasad R. Joshi, Asha Suryanarayanan, Eszter Hazai, Marvin K. Schulte, G. Maksay, Zsolt Bikádi

Research output: Contribution to journalArticle

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Abstract

A new homology model of type-3A serotonin receptors (5-HT3ARs) was built on the basis of the electron microscopic structure of the nicotinic acetylcholine receptor and with an agonist-free binding cavity. The new model was used to re-evaluate the interactions of granisetron, a 5-HT3AR antagonist. Docking of granisetron identified two possible binding modes, including a newly identified region for antagonists formed by loop B, C, and E residues. Amino acid residues L184-D189 in loop B were mutated to alanine, while Y143 and Y153 in loop E were mutated to phenylalanine. Mutation H185A resulted in no detectable granisetron binding, while D189A resulted in a 22-fold reduction in affinity. Y143F and Y153F decreased granisetron affinity to the same extent as Y143A and Y153A mutations, supporting the role of the OH groups of these tyrosines in loop E. Modeling and mutation studies suggest that granisetron plays its antagonist role by hindering the closure of the back wall of the binding cavity.

Original languageEnglish
Pages (from-to)1099-1105
Number of pages7
JournalBiochemistry
Volume45
Issue number4
DOIs
Publication statusPublished - Jan 31 2006

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Granisetron
Mutation
Nicotinic Receptors
Phenylalanine
Alanine
Tyrosine
Electrons
Amino Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Joshi, P. R., Suryanarayanan, A., Hazai, E., Schulte, M. K., Maksay, G., & Bikádi, Z. (2006). Interactions of granisetron with an agonist-free 5-HT3A receptor model. Biochemistry, 45(4), 1099-1105. https://doi.org/10.1021/bi051676f

Interactions of granisetron with an agonist-free 5-HT3A receptor model. / Joshi, Prasad R.; Suryanarayanan, Asha; Hazai, Eszter; Schulte, Marvin K.; Maksay, G.; Bikádi, Zsolt.

In: Biochemistry, Vol. 45, No. 4, 31.01.2006, p. 1099-1105.

Research output: Contribution to journalArticle

Joshi, PR, Suryanarayanan, A, Hazai, E, Schulte, MK, Maksay, G & Bikádi, Z 2006, 'Interactions of granisetron with an agonist-free 5-HT3A receptor model', Biochemistry, vol. 45, no. 4, pp. 1099-1105. https://doi.org/10.1021/bi051676f
Joshi PR, Suryanarayanan A, Hazai E, Schulte MK, Maksay G, Bikádi Z. Interactions of granisetron with an agonist-free 5-HT3A receptor model. Biochemistry. 2006 Jan 31;45(4):1099-1105. https://doi.org/10.1021/bi051676f
Joshi, Prasad R. ; Suryanarayanan, Asha ; Hazai, Eszter ; Schulte, Marvin K. ; Maksay, G. ; Bikádi, Zsolt. / Interactions of granisetron with an agonist-free 5-HT3A receptor model. In: Biochemistry. 2006 ; Vol. 45, No. 4. pp. 1099-1105.
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