Structured and disordered facets of the GPCR fold.

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• G-protein coupled receptors (GPCRs) are integral membrane proteins with a conserved seven-transmembrane (7TM) helix structure.
• These receptors mediate a vast array of physiological signaling processes, making them critical drug targets.

Purpose of the Study:

• To analyze the diversity of structured and disordered regions across all human GPCRs.
• To compare structural features and ligand-binding sites among different GPCR classes.
• To elucidate the role of disordered regions in GPCR signaling.

Main Methods:

• Analysis of recently published crystal structures of GPCRs.
• Systematic sequence analysis of all human GPCRs.
• Comparative structural analysis of rhodopsin-like (class A), secretin-like (class B), metabotropic (class C), and frizzled (class F) receptors.

Main Results:

• Transmembrane helix arrangement is conserved across major GPCR classes, but ligand binding sites vary.
• GPCR sequences reveal disordered cytoplasmic segments, numerous post-translational modification sites, and alternative splicing.
• Putative linear peptide motifs suggest interactions with cytosolic proteins.

Conclusions:

• Structured regions of GPCRs bind diverse ligands, while disordered regions play a significant role in modulating downstream signaling.
• An integrated understanding of both structured and disordered regions is essential for comprehending GPCR structure-function relationships.