SUSTech Research Group Makes Breakthrough in Anti-Inflammatory Drugs
Original link: http://www.sustc.edu.cn/en/news_events_1_6/2732
Associate Professor Wei Zhiyi from the Department of Biology at Southern University of Science and Technology (SUSTech) has published two papers with his colleague Assistant Professor Zhang Cheng from the Department of Medicine at the University of Pittsburgh. Their papers were published in Cell magazine’s "Molecular Cell" and Nature magazine’s "Nature Structural & Molecular Biology." Two important G-protein coupled receptors (GPCRs) have been reported to bind to the high-resolution three-dimensional structure of many different antagonists, and the ligand-binding mechanism and activation mechanism of these two GPCRs have been elucidated. As a result, a new idea has been proposed for the development of anti-allergy and anti-inflammatory drugs targeting the two GPCR proteins.
Wei Zhiyi is a high-level overseas talent who joined SUSTech in October 2013. He has been active in the field of structural biology for a long time. He is dedicated to exploring the molecular mechanisms of neural development in the brain, as well as the assembly mechanism and target recognition mechanism of molecular protein machines. He has published more than 50 research papers. Among them, he has published six papers in high-impact international journals such as Nature, Molecular Cell, and PNAS as correspondents.
GPCRs are a large number of cell surface receptor proteins that sense extracellular signals and transmit signals to cells. When an extracellular signal molecule binds to a GPCR, it causes a conformational change in the GPCR and activates a downstream signaling pathway. Because GPCR is widely involved in the regulation of human physiological and pathological activities, GPCR is not only a hotspot in life science research but also the darling of major pharmaceutical companies. Among the new drugs approved by the US Food and Drug Administration (FDA), new drugs targeting GPCR account for one-third of the total. However, due to the nature of GPCR, it is highly dynamic, which makes the GPCR structure analysis very challenging, restricts the understanding of GPCR-mediated cell signaling mechanism, and limits the development of drugs targeting GPCR.
On the left, CRTH2 binds to two antagonist molecules; the right panel shows the binding of CRTH2 to the native ligand PGD2. (cited from Wang et al. Molecular Cell, 2018)
Wei Zhiyi and Zhang Cheng's research team published a research paper entitled "Structures of the human PGD2 receptor CRTH2 reveal novel mechanisms for ligand recognition" on "Molecular Cell." As a GPCR, CRTH2 is a receptor for the endogenous lipid prostaglandin PGD2. The signaling of prostaglandin D2 (PGD2) through a G-protein-coupled receptor (GPCR) CRTH2 is a major pathway in type 2 inflammation. Compelling evidence suggests the therapeutic benefits of blocking CRTH2 signaling in many inflammatory disorders. Currently, a number of CRTH2 antagonists are under clinical investigation, and one compound, fevipiprant, has advanced to phase 3 clinical trials for asthma. Here, we present the crystal structures of human CRTH2 with two antagonists, fevipiprant and CAY10471. The structures, together with docking and ligand-binding data, reveal a semi-occluded pocket covered by a well-structured amino terminus and different binding modes of chemically diverse CRTH2 antagonists. Structural analysis suggests a ligand entry port and a binding process that is facilitated by opposite charge attraction for PGD2, which differs significantly from the binding pose and binding environment of lysophospholipids and endocannabinoids, revealing a new mechanism for lipid recognition by GPCRs.
On June 25, the research team also successfully analyzed the crystal structure of another kind of GPCR protein, C5aR, that can cause a strong inflammatory reaction. They explained the ligand binding mode and activation mechanism of C5aR, in order to propose a new strategy for the design of various anti-inflammatory drug molecules targeting C5aR. This research was published in "Nature Structural & Molecular Biology" under the title "Orthosteric and allosteric action of the C5a receptor antagonists". Wei Zhiyi is involved in the structural analysis, thesis writing and is the co-author of this article.
The above research projects have been funded by the National Natural Science Foundation of China, and the Southern University of Science and Technology.
The Newshub interviewed Professor Wei Zhiyi, to get the story behind the research results.
Q: Congratulations to you and the research team for publishing two research papers in the Cell and Nature sub-journals! How could you get two papers published in such a short period of time?
A: This is the result of many years of hard work. In fact, we launched both these projects many years ago. It’s extremely difficult to obtain stable GPCR protein samples. The proteins also need to be processed and modified. Such a process requires a lot of experimentation to be successful. In the early period, Professor Zhang Cheng obtained a sample of GPCR proteins that could be used for structural analysis through a long period of exploration and experimentation. After that, we continued to optimize the crystals of these GPCR proteins and tried to resolve the crystal structure. We finally obtained the results we needed that can be used for publication.
Q: Is the research team led by Zhang Cheng still engaged in other cooperation?
A: I am good friends with Professor Zhang Cheng. We also support and help each other through our collaborative research. We are currently working together on a number of collaborative projects, all of which focus on the structural biology of GPCR.
Q: Why are you interested in researching GPCRs? What projects will the team move on to next?
A: It is essential for many physiological and pathological activities in the human body. For example, the two GPCR proteins we studied are involved in the regulation of inflammatory responses. Some inflammation can lead to serious diseases such as asthma. Studying the structure of these GPCRs not only allows us to understand the working mechanism of these miraculous receptor molecules but also promotes the treatment of related diseases. As a result, it is an excellent combination of both basic and applied research.