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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
Published on: September 13, 2013
Engineering G protein-coupled receptors to facilitate their structure determination
Christopher G Tate1, Gebhard F X Schertler
1MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK. cgt@mrc-lmb.cam.ac.uk
Current Opinion in Structural Biology
|August 18, 2009
Summary
Ten new high-resolution G protein-coupled receptor (GPCR) structures reveal conserved interaction networks crucial for receptor activation. These findings offer new strategies for determining membrane protein structures and understanding GPCR signaling mechanisms.
Area of Science:
- Structural biology
- Biochemistry
- Molecular pharmacology
Background:
- G protein-coupled receptors (GPCRs) are critical cell surface receptors involved in numerous physiological processes.
- Understanding GPCR structure and activation mechanisms is essential for drug development.
- Recent advancements have enabled high-resolution structural determination of various GPCRs.
Purpose of the Study:
- To present 10 new high-resolution structures of GPCRs, including opsin, rhodopsin mutants, beta-adrenergic receptors, and adenosine A2a receptor.
- To elucidate conserved interaction networks within GPCRs important for structure and activation.
- To provide new strategies for GPCR structure determination applicable to other membrane proteins.
Main Methods:
- High-resolution structure determination using X-ray crystallography.
- Heterologous expression of engineered GPCRs in insect and mammalian cells.
- Purification of proteins from native sources (bovine opsin, squid rhodopsin).
Main Results:
- 10 new high-resolution GPCR structures solved, including antagonist-bound and active-like states.
- Identification of conserved residue interaction networks critical for GPCR structure and activation.
- Elucidation of the interaction between a conserved residue (Arg135) and the G protein alpha-subunit, providing insights into G protein activation.
Conclusions:
- New strategies for membrane protein structure determination have been developed.
- Conserved interaction networks offer a framework for understanding GPCR activation mechanisms.
- The structural basis for G protein activation by GPCRs is beginning to be elucidated.
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