Editors' ChoiceStructural Biology

Brains Over Brawn

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Science Signaling  31 Mar 2009:
Vol. 2, Issue 64, pp. ec110
DOI: 10.1126/scisignal.264ec110

Ligands bind to nicotinic acetylcholine receptors (AChRs) in a site known as the “aromatic box” because it contains aromatic amino acids. Nicotine binds with much greater affinity to the AChR subtype in brain (α4β2), which is thought to be involved in nicotine addiction, than it does to the subtype in muscle (α1β1). Nicotine forms a cation-π interaction with Trp149 (called TrpB) in the aromatic box in brain, but not muscle, AChRs; however, the reason for this difference has been unclear because the sequence of the aromatic box in both subtypes is identical. (A cation-π interaction is a noncovalent association between a cation and an electron-rich π system, such as the side chain of a tryptophan residue.) Xiu et al. substituted fluorinated amino acid analogs (which would be expected to weaken cation-π interactions) at the TrpB residue position in α1β1 or α4β2 AChRs expressed in Xenopus oocytes and observed that these unnatural amino acids affected binding of ACh and nicotine to the α4β2 brain subtype but not the α1β1 muscle subtype, thus confirming the presence of a strong cation-π interaction in the former and its absence in the latter. The brain receptor contains Lys in the position four residues from TrpB, whereas the muscle receptor contains Gly in this position. Muscle receptors containing this mutation (Gly153→Lys153) exhibited a strong cation-π interaction with nicotine. Based on previous work showing that the carbonyl backbone of TrpB forms a hydrogen bond with nicotine, the authors propose that the Lys153 residue in α4β2 brain receptors alters the shape of the aromatic box such that nicotine can get closer and bind strongly to TrpB. Indeed, the α7 nicotinic receptor, which has a lower affinity for nicotine than the α4β2 subtype, contains Gly at position 153. This knowledge may assist in the design of drugs that target specific nicotinic receptor subtypes.

X. Xiu, N. L. Puskar, J. A. P. Shanata, H. A. Lester, D. A. Dougherty, Nicotine binding to brain receptors requires a strong cation–π interaction. Nature 458, 534–537 (2009). [PubMed]

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