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

  • Ralf Christian Kling
  • Carolin Burchardt
  • Jürgen Einsiedel
  • Harald Hübner
  • Peter GmeinerEmail author
Original Paper
Part of the following topical collections:
  1. Tim Clark 70th Birthday Festschrift


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.


Structure-based drug design Allosteric binding pocket Neurotensin receptor GPCR ligands Peptide Subtype selectivity Molecular dynamics simulations SPPS 


Supplementary material

894_2019_4064_MOESM1_ESM.docx (10 mb)
ESM 1 (DOCX 10271 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ralf Christian Kling
    • 1
    • 2
  • Carolin Burchardt
    • 1
  • Jürgen Einsiedel
    • 1
  • Harald Hübner
    • 1
  • Peter Gmeiner
    • 1
    Email author
  1. 1.Department of Chemistry and PharmacyFriedrich Alexander UniversityErlangenGermany
  2. 2.ABF-Pharmazie GmbHFürthGermany

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