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Structural basis of ligand recognition in 5-HT3 receptors
- Kesters, D. (author)
- Thompson, A. J. (author)
- Brams, M. (author)
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- Van Elk, R. (author)
- Spurny, R. (author)
- Geitmann, M. (author)
- Villalgordo, J. M. (author)
- Guskov, A. (author)
- Lummis, S. C. R. (author)
- Smit, A. B. (author)
- Ulens, C. (author)
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- (creator_code:org_t)
- 2012-11-30
- 2013
- English.
- In: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 14:1, s. 49-56
- Journal article (peer-reviewed)
Abstract
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- 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.
Keyword
- 5-hydroxytryptamine-3 receptor
- Cys-loop receptor
- pentameric ligand-gated ion channel
- serotonin
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- Kesters, D.
- Thompson, A. J.
- Brams, M.
- Van Elk, R.
- Spurny, R.
- Geitmann, M.
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- Villalgordo, J. ...
- Guskov, A.
- Danielson, Helen ...
- Lummis, S. C. R.
- Smit, A. B.
- Ulens, C.
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- EMBO Reports
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- Uppsala University
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