A team of scientists in Shanghai has determined a high-resolution multi-domain human smoothened receptor structure, a validated therapeutic target for cancer. The results illustrate the allosteric domain-domain interactions and their role in smoothened activation. These new findings are published on May 17 2017 (17:00PM, Beijing time) in Nature Communications, titled “Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand” (https://www.nature.com/articles/ncomms15383).
As a central player in the Hedgehog signaling pathway, a system that is actively involved in the embryonic development and tumorigenesis, the smoothened receptor (SMO) has been long sought after as a drug target for numerous malignancies. SMO belongs to the Frizzled class of G protein-coupled receptors (GPCRs) containing a characteristic extracellular cysteine-rich domain (CRD) in addition to the canonical seven-transmembrane helices domain (TMD). Past drug discovery efforts on SMO have yielded many effective anti-tumor agents, yet problems with their long-term use exist due to the development of resistance. All these drugs bind to the orthostatic ligand binding site on the TMD. “Development of next generation therapeutics targeting SMO will be facilitated by understanding of the multi-domain arrangement in the receptor structure”, said Fei Xu, Research Associate Professor at iHuman Institute, ShanghaiTech University, and the lead corresponding author of this paper. “This structure will allow us to identify potentially new ligand binding sites and signaling mechanisms.”
In addition to the CRD and TMD, this structure also reveals a third domain, i.e., the hinge domain (HD) that may possess modulating functions not only in connecting the CRD with TMD, but also in facilitating signal transduction from the extracellular to the intracellular side of SMO. The role of the HD is further assessed by mutagenesis and pharmacological analysis carried out by Dr. Wenfu Tan’s group at School of Pharmacy, Fudan University. “Identification of the HD may provide hints for the development of new modulators targeting on this region”, he commented.
Dr. Houchao Tao of ShanghaiTech University and two graduate students (Xianjun Zhang and Jun Yang), among others, participated in the study. Financial support to this work was provided by ShanghaiTech University, the National “Young Thousand Talents” Program, Shanghai “Pujiang Talent” Program and the National Natural Science Foundation of China.
The crystal structure of multi-domain human Smoothened receptor (PDB ID: 5V56). The cysteine-rich domain (CRD), transmembrane domain (TMD) and hinge domain (HD) are shown in orange, light blue and green, respectively. The ligand TC114 is shown as spheres in magenta.
