The molecular basis of subtype selectivity of human kinin G-protein-coupled receptors

Nat Chem Biol. 2018 Mar;14(3):284-290. doi: 10.1038/nchembio.2551. Epub 2018 Jan 15.

Abstract

G-protein-coupled receptors (GPCRs) are the most important signal transducers in higher eukaryotes. Despite considerable progress, the molecular basis of subtype-specific ligand selectivity, especially for peptide receptors, remains unknown. Here, by integrating DNP-enhanced solid-state NMR spectroscopy with advanced molecular modeling and docking, the mechanism of the subtype selectivity of human bradykinin receptors for their peptide agonists has been resolved. The conserved middle segments of the bound peptides show distinct conformations that result in different presentations of their N and C termini toward their receptors. Analysis of the peptide-receptor interfaces reveals that the charged N-terminal residues of the peptides are mainly selected through electrostatic interactions, whereas the C-terminal segments are recognized via both conformations and interactions. The detailed molecular picture obtained by this approach opens a new gateway for exploring the complex conformational and chemical space of peptides and peptide analogs for designing GPCR subtype-selective biochemical tools and drugs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • HEK293 Cells
  • Humans
  • Insecta
  • Kinins / chemistry*
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Docking Simulation
  • Mutation
  • Peptides / chemistry
  • Protein Binding
  • Protein Domains
  • Protein Structure, Secondary
  • Receptor, Bradykinin B1 / chemistry*
  • Receptor, Bradykinin B2 / chemistry*
  • Receptors, G-Protein-Coupled / chemistry*
  • Sf9 Cells
  • Signal Transduction
  • Static Electricity*

Substances

  • Kinins
  • Ligands
  • Peptides
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Receptors, G-Protein-Coupled