Kling R, Burchardt C, Einsiedel J, Hübner H, Gmeiner P (2019)
Publication Type: Journal article
Publication year: 2019
Book Volume: 25
Article Number: 193
Journal Issue: 7
DOI: 10.1007/s00894-019-4064-x
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.
APA:
Kling, R., Burchardt, C., Einsiedel, J., Hübner, H., & Gmeiner, P. (2019). Structure-based exploration of an allosteric binding pocket in the NTS1 receptor using bitopic NT(8-13) derivatives and molecular dynamics simulations. Journal of Molecular Modeling, 25(7). https://dx.doi.org/10.1007/s00894-019-4064-x
MLA:
Kling, Ralf, et al. "Structure-based exploration of an allosteric binding pocket in the NTS1 receptor using bitopic NT(8-13) derivatives and molecular dynamics simulations." Journal of Molecular Modeling 25.7 (2019).
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