Different binding orientations for the same agonist at homologous receptors: a lock and key or a simple wedge?

J Am Chem Soc. 2003 Jun 11;125(23):6850-1. doi: 10.1021/ja0348086.

Abstract

Using unnatural amino acid mutagenesis, the binding site for serotonin at the novel Caenorhabditis elegans receptor MOD-1 has been probed. As with the closely related serotonin receptor 5-HT3, MOD-1 makes use of a strong cation-pi interaction between the ammonium of serotonin and the indole side chain of a tryptophan. However, the specific Trp used by MOD-1 is different from that used for 5-HT3 (and the nAChR), aligning with a residue more than 40 amino acids distant in sequence space and on a different "loop" of the agonist binding site. This suggests a significant rearrangement of the ligand on binding these two closely related receptors. It is suggested that, unlike enzymes, receptors and other signaling molecules may need only to deliver an agonist to a general binding region, rather than establishing precise drug-receptor interactions.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Caenorhabditis elegans Proteins*
  • Chloride Channel Agonists
  • Chloride Channels / chemistry*
  • Chloride Channels / metabolism
  • Kinetics
  • Models, Molecular
  • Nicotinic Agonists / chemistry*
  • Nicotinic Agonists / metabolism
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / metabolism
  • Receptors, Serotonin / chemistry*
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT3
  • Serotonin Receptor Agonists / chemistry*
  • Serotonin Receptor Agonists / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Chloride Channel Agonists
  • Chloride Channels
  • MOD-1 protein, C elegans
  • Nicotinic Agonists
  • Receptors, Nicotinic
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Receptor Agonists