Closing the ring: a fourth extracellular loop in chemokine receptors

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Pharmacology

Background:

• Chemokine receptors are crucial G protein-coupled receptors (GPCRs) involved in numerous physiological and pathological processes.
• Their typical structure includes a seven-transmembrane helix bundle stabilized by a disulfide bond between TM3 and ECL2.

Purpose of the Study:

• To investigate the structural features of chemokine receptors, specifically focusing on a newly identified second disulfide bridge.
• To elucidate the formation, characteristics, and functional implications of the resulting extracellular loops.

Main Methods:

• Analysis of the three-dimensional structures of chemokine receptors CXCR1, CXCR4, and CCR5.
• Identification and characterization of a second disulfide bond linking the N terminus to TM7.

Main Results:

• A second disulfide bridge was discovered in CXCR1, CXCR4, and CCR5, connecting the N terminus to TM7.
• This bridge forms additional extracellular loops, termed "pseudo-loops," which modify the ligand-binding pocket entrance.
• These pseudo-loops enhance receptor surface rigidity.

Conclusions:

• The second disulfide bond is a significant structural feature of certain chemokine receptors.
• Pseudo-loops play a role in shaping the ligand-binding site and contribute to receptor stability.
• Understanding these structural elements is key to comprehending chemokine receptor function and developing targeted therapeutics.