5LXB: Crystal Structure Of A Mutant Binding Protein (5htbp-achbp) In Complex With Palonosetron

Citation:
Abstract
Palonosetron is a potent 5-HT3 receptor antagonist and an effective therapeutic agent against emesis. Here we identify the molecular determinants of compound recognition in the receptor binding site by obtaining a high resolution structure of palonosetron bound to an engineered acetylcholine binding protein that mimics the 5-HT3 receptor binding site, termed 5-HTBP, and by examining the potency of palonosetron in a range of 5-HT3 receptors with mutated binding site residues. The structural data indicate that palonosetron forms a tight and effective wedge in the binding pocket, made possible by its rigid tricyclic ring structure and its interactions with binding site residues; it adopts a binding pose that is distinct from the related antiemetics granisetron and tropisetron. The functional data show many residues previously shown to interact with agonists and antagonists in the binding site are important for palonosetron binding, and indicate those of particular importance are W183 (a cation-pi interaction and a hydrogen bond) and Y153 (a hydrogen bond). This information, and the availability of the structure of palonosetron bound to 5-HTBP, should aid the development of novel and more efficacious drugs that act via 5-HT3 receptors.
PDB ID: 5LXBDownload
MMDB ID: 144031
PDB Deposition Date: 2016/9/20
Updated in MMDB: 2016/10
Experimental Method:
x-ray diffraction
Resolution: 2.34  Å
Source Organism:
Similar Structures:
Biological Unit for 5LXB: pentameric; determined by software (PISA)
Molecular Components in 5LXB
Label Count Molecule
Proteins (5 molecules)
5
Soluble Acetylcholine Receptor
Molecule annotation
Chemicals (8 molecules)
1
4
2
4
* Click molecule labels to explore molecular sequence information.

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