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Molecular basis for high-affinity agonist binding in GPCRs.

Tony Warne1, Patricia C Edwards1, Andrew S Doré2

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Summary
This summary is machine-generated.

G protein-coupled receptors (GPCRs) show higher agonist affinity in their active state. Structural analysis reveals a smaller binding site and increased atomic contacts, explaining this enhanced affinity.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) are crucial cell surface receptors.
  • GPCRs exhibit higher affinity for agonists in their active conformation compared to their inactive state.
  • The molecular mechanisms underlying this affinity difference remain incompletely understood.

Purpose of the Study:

  • To elucidate the structural basis for increased agonist affinity in the active state of GPCRs.
  • To compare the active and inactive states of the β1-adrenoceptor (β1AR) bound to agonists.

Main Methods:

  • Determined four active-state structures of β1AR complexed with conformation-specific nanobodies and agonists of varying efficacy.
  • Compared these active-state structures with previously determined inactive-state structures of β1AR bound to the same ligands.

Main Results:

  • A significant reduction (24-42%) in the orthosteric binding site volume was observed in the active state compared to the inactive state.
  • Potential hydrogen bonds between the receptor and ligand were found to be shorter in the active state.
  • An increase (up to 30%) in atomic contacts between the β1AR and the ligand was noted in the active conformation.

Conclusions:

  • The smaller, more constrained binding pocket in the active state of β1AR leads to increased atomic contacts and shorter hydrogen bonds.
  • These structural changes provide a molecular explanation for the enhanced agonist affinity observed in active GPCRs.
  • The findings are applicable to a broad range of structurally diverse agonists binding to GPCRs.