Breakthrough by local scientists may lead to better cancer drugs

An "orphan receptor" breakthrough by local scientists is providing new insights into developing more effective cancer drugs.

G protein-coupled receptors, or GPCRs, play a crucial role in cell signaling, which helps locate target molecules. Roughly 40 percent of drugs on the market work through GPCRs, making it the largest drug-target protein family.

Although breakthroughs in GPCR structural and pharmacological studies have been popping up, more than 100 GPCRs remain "orphan receptors" whose ligands (an ion or molecule that binds to a central metal atom to form a coordination complex) and signaling pathways have not yet been identified.

Lack of comprehensive understanding about GPCRs has hindered the progress of developing drugs that target GPCRs. However, a joint research team has shed light on the way orphan receptors activate themselves.

The research, led by Wu Beili and Zhao Qiang from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, in cooperation with Shui Wenqing's team at ShanghaiTech University, has been published in the leading scientific journal "Nature."

Researchers used cryo-electron microscopy (cryo-EM) to unravel the three-dimensional structures of complexes composed of G proteins and two "orphans" in the adhesion receptors family: ADGRD1 and ADGRF1.

Adhesion GPCRs, a family of 33 receptors, are active in a variety of physiological processes, including immune response, organ development and cellular communication, and are implicated in many diseases such as schizophrenia, hyperactivity and cancer. They are currently the least understood class of GPCRs.

Researchers focused on ADGRD1 and ADGRF1, believed to contribute to several different kinds of cancer.

By studying the G protein-bound structures of ADGRD1 and ADGRF1, they found a unique self-activating process exclusive to adhesion GPCRs.

The study shows a peptide segment, known as "stalk," works as an endogenous agonist. It interacts with transmembrane domain (a membrane-spanning protein part of receptor) and changes the shape of transmembrane helices, in turn activating receptors to bind to G proteins.

Liu Zhijie, head of the iHuman Institute at ShanghaiTech University, said the study for the first time uncovers key molecular factors that govern the intrinsic activation of adhesion receptors, providing essential insights into the signal transduction mechanism of this GPCR family and offering new clues for drug design and discovery.