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Structure-based exploration of an allosteric binding pocket in the NTS1 receptor using bitopic NT(8-13) derivatives and molecular dynamics simulations

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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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  1. Ralf Christian Kling

    Present address: ABF-Pharmazie GmbH, Nürnberger Straße 22, 90762, Fürth, Germany

Authors and Affiliations

  1. Department of Chemistry and Pharmacy, Friedrich Alexander University, Nikolaus-Fiebiger-Straße 10, 91058, Erlangen, Germany

    Ralf Christian Kling, Carolin Burchardt, Jürgen Einsiedel, Harald Hübner & Peter Gmeiner

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  1. Ralf Christian Kling
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  2. Carolin Burchardt
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  4. Harald Hübner
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Correspondence to Peter Gmeiner.

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Kling, R.C., Burchardt, C., Einsiedel, J. et al. Structure-based exploration of an allosteric binding pocket in the NTS1 receptor using bitopic NT(8-13) derivatives and molecular dynamics simulations. J Mol Model 25, 193 (2019). https://doi.org/10.1007/s00894-019-4064-x

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