Background

Ligands

Significance

Structure

Heterotrimeric G-Protein Structure

Novel Characteristics

MRGPRX2 demonstrates novel characteristics compared to other class A GPCRs. These structural motif differences contribute to a surface ligand binding rather than a ligand binding deep within the helices. To demonstrate this difference in depth binding, MRGPRX2 is compared to 5HT2AR, another class A GPCR with more conserved structural motifs.

Comparison of ligand Cortistatin-14 binding in MRGPRX2 (left) and binding in 5HT2AR (right)

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PIF/LLF Motif

DRY/ ERC Motif

MRGPRX2 has an rather than the typically conserved E/DRY Motif. The amino acid residue shift from TYR-174 to CYS-128 has spatial arrangement implications where the helices are more compact in MRGPRX2 without the TYR to physically push the TMP helices apart.

ERC Motif

Sodium Site

The MRGPRX2 consists of ASP-75 and GLY-116 compared to the previously conserved residues in this binding pocket. Other class A GPCRs demonstrate a larger binding pocket with a higher negative character allowing for a suitable environment for sodium ions to bind. In MRGPRX2, this pocket lacks the same amount of with the shift to a glycine residue rather than typical negative residues. The helices for the MRGPRX2 in the binding pocket are also more collapsed making this pocket less accessible for sodium ions.

Disulfide Bonds

Further Information

NPxxY Motif

The in the NPxxY motif are pivotal for receptor activation in all Class A GPCRs. This motif is conserved in the MRGPRX2 receptor with residues VAL-231, ASP-75, ASN-275, and TYR-279.

Function

Before Activation

After Activation

Clinical Relevance

3D Structures

References