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Ligand binding and micro-switches in 7TM receptor structures.

Rie Nygaard¹, Thomas M Frimurer, Birgitte Holst

¹Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, DK-2200, Denmark.

Trends in Pharmacological Sciences

|April 21, 2009

Summary

Novel X-ray structures reveal seven transmembrane (7TM) receptors have a funnel-shaped binding pocket. Conserved residues act as micro-switches, connecting ligand binding to intracellular signaling via an allosteric interface.

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Area of Science:

Structural biology
Biochemistry
Pharmacology

Background:

Recent years have yielded new X-ray structures of seven transmembrane (7TM) receptors.
These structures include complexes with antagonists and G protein fragments.

Purpose of the Study:

To analyze the structural basis of ligand binding and G protein interaction in 7TM receptors.
To elucidate the role of conserved residues and allosteric interfaces in signal transduction.

Main Methods:

X-ray crystallography to determine high-resolution structures.
Analysis of ligand-bound and G protein-complexed 7TM receptor structures.

Main Results:

7TM receptors possess a funnel-shaped ligand-binding pocket with extracellular loop 2b acting as a gate.
Small-molecule antagonists bind in diverse modes, from deep within the pocket to superficially.
Conserved residues, like Arg3.50, function as micro-switches, crucial for G protein interaction.
An extended allosteric interface involving micro-switches and hydrogen bonds facilitates signal transduction.

Conclusions:

The structural insights explain how ligand binding is translated into intracellular signaling.
Understanding these mechanisms is key for developing targeted therapeutics for 7TM receptor-related diseases.