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Structurally defining neurokinin selectivity to improve NK2R agonists.

Artem Pavlovskyi1, Yinhang Ren2,3,4, María Gestal-Mato1

  • 1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

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Researchers identified key interactions for neurokinin 2 receptor (NK2R) agonists to improve obesity pharmacotherapies. Understanding NK2R selectivity is crucial for developing drugs that both reduce food intake and increase energy expenditure.

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Area of Science:

  • Pharmacology
  • Structural Biology
  • Metabolic Research

Background:

  • Incretin-based obesity drugs primarily reduce food intake, limiting efficacy.
  • Increasing energy expenditure is a promising but challenging therapeutic strategy.
  • Neurokinin 2 receptor (NK2R) activation shows potential for both reducing food intake and stimulating energy expenditure.

Purpose of the Study:

  • To understand the structural basis of NK2R selectivity for developing improved obesity pharmacotherapies.
  • To identify specific interactions between NK2R and its ligands that drive selectivity.
  • To enable the design of novel NK2R agonists with enhanced therapeutic profiles.

Main Methods:

  • Cryo-electron microscopy was used to determine the structure of NK2R bound to its endogenous ligand and synthetic agonists.
  • Structure-based analysis identified key residues in the NK2R binding pocket and ligand C-terminus responsible for selectivity.
  • Site-directed mutagenesis of the receptor and ligands was performed to functionally validate these interactions.

Main Results:

  • Cryo-EM structures revealed specific binding interactions governing NK2R selectivity.
  • Mutagenesis studies confirmed the role of identified residues in receptor-ligand interactions and selectivity.
  • A structural framework for neurokinin selectivity was established.

Conclusions:

  • Understanding NK2R binding interactions is key to developing selective agonists.
  • This structural insight facilitates the design of next-generation NK2R-based obesity treatments.
  • Targeted development of NK2R agonists can improve therapeutic efficacy by modulating both food intake and energy expenditure.