AI Article Synopsis
- Crystal structures of neurotensin receptor subtype 1 (NTS1) helped identify how the neurotensin peptide and its active fragment fit into the receptor's binding site.
- Researchers discovered a unique allosteric binding pocket in NTS1 that differs from NTS2 and explored it using modified peptides, which improved their ability to selectively activate NTS1.
- The study found that while the binding mode in the main site remains consistent, the newly identified allosteric pocket shows flexibility, allowing it to accommodate different residues from modified peptides.
Article Abstract
Crystal structures of neurotensin receptor subtype 1 (NTS1) allowed us to visualize the binding mode of the endogenous peptide hormone neurotensin and its pharmacologically active C-terminal fragment NT(8-13) within the orthosteric binding pocket of NTS1. Beneath the orthosteric binding pocket, we detected a cavity that exhibits different sequences in the neurotensin receptor subtypes NTS1 and NTS2. In this study, we explored this allosteric binding pocket using bitopic test peptides of type NT(8-13)-Xaa, in which the C-terminal part of NT(8-13) is connected to different amino acids that extend into the newly discovered pocket. Our test compounds showed nanomolar affinities for NTS1, a measurable increase in subtype selectivity compared to the parent peptide NT(8-13), and the capacity to activate the receptor in an IP accumulation assay. Computational investigation of the selected test compounds at NTS1 showed a conserved binding mode within the orthosteric binding pocket, whereas the allosteric cavity was able to adapt to different residues, which suggests a high degree of structural plasticity within that cavity of NTS1.
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| http://dx.doi.org/10.1007/s00894-019-4064-x | DOI Listing |
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