The activation mechanism and antibody binding mode for orphan GPR20

Related Experiment Video

Updated: Aug 8, 2025

Characterization of Glycoproteins with the Immunoglobulin Fold by X-Ray Crystallography and Biophysical Techniques
08:58

Characterization of Glycoproteins with the Immunoglobulin Fold by X-Ray Crystallography and Biophysical Techniques

Published on: July 5, 2018

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Xi Lin1, Shan Jiang1,2, Yiran Wu1

  • 1iHuman Institute, ShanghaiTech University, Pudong, Shanghai, China.

Cell Discovery
|February 27, 2023
PubMed

Insights

Gastrointestinal stromal tumor (GIST) target GPR20

Area of Science:

  • Structural biology
  • G protein-coupled receptors
  • Oncology

Background:

  • GPR20 is an orphan receptor overexpressed in GIST, making it a therapeutic target.
  • A GPR20-binding antibody-drug conjugate (ADC), Ab046, is in clinical trials for GIST.
  • The mechanism behind GPR20's high basal activity is unknown.

Purpose of the Study:

  • To elucidate the structural basis of GPR20's basal activity.
  • To characterize the interaction between GPR20 and the Ab046 antibody.
  • To identify potential sites for GPR20 ligand binding.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine GPR20 structures.
  • Mutagenesis studies to investigate GPR20 function.
  • Structural analysis of GPR20-Gi and GPR20-Ab046 complexes.

Main Results:

  • Three cryo-EM structures of human GPR20 complexes were determined.
  • A unique N-terminal helix capping the transmembrane domain was identified as crucial for basal activity.
  • Molecular interactions between GPR20 and Ab046 were revealed.
  • An unassigned density in the orthosteric pocket suggests a potential binding site.

Conclusions:

  • The N-terminal helix plays a key role in GPR20's constitutive Gi activation.
  • Structural insights enable the design of improved GPR20-targeting antibodies.
  • Further investigation of the orthosteric pocket may lead to GPR20 deorphanization.

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