Xuewu Zhang, professor of pharmacology and biophysics at University of Texas Southwestern Medical Center, will give an Apex Lecture on March 4 at 4:15 p.m. CT in 1220 MRB III. A reception will immediately follow the lecture in the MRB III first-floor atrium.
His talk, “Structures of the Innate Immunity Adaptor STING: From Mechanisms to Potential Therapeutics,” is co-sponsored by the Department of Pharmacology.
Zhang earned his graduate degree from the Albert Einstein College of Medicine under renowned immunologist Stanley Nathenson and served as a postdoctoral associate in the lab of dean of Basic Sciences John Kuriyan, then at the University of California, Berkeley. Zhang is currently a professor in the Department of Pharmacology at UT Southwestern.
The Zhang lab aims to understand mechanisms for the regulation of signaling proteins through intra- and inter-molecular interactions. A major focus is on receptor-mediated signaling pathways involved in neuron development and axonal guidance and more recently on those involved in innate immunity. Zhang uses biochemistry, X-ray crystallography, cryo-EM, and cell biological approaches to seek understanding of regulatory mechanisms at the atomic level.
“Dr. Zhang is a pioneering structural biologist with numerous groundbreaking contributions to our current understanding of signal transduction mechanisms,” Ege Kavalali said. . “In particular, he provided seminal insight into how extracellular ligands interact with membrane receptors and direct cellular signaling.” Kavalali is the chair of the Department of Pharmacology.
Zhang has shown that the intracellular region of a protein called plexin has GTPase activating protein activity specific to the Ras homolog Rap and that this activity is critical for its signaling. More recently, Zhang and collaborators have determined the cryo-EM structures of full-length STING and the STING/TBK1 complex, which provide detailed molecular views of full-length STING in both the inactive and cGAMP-bound active states and of its interaction with TBK1. These data allowed Zhang to propose a complete model of the activation of STING by cGAMP and the subsequent recruitment and activation of TBK1.
About the Apex Lecture Series
There are major inflection points in biomedical discovery that create new fields, new ideas, and new opportunities to impact human health. To engage with global researchers contributing to these inflection points, the Vanderbilt School of Medicine Basic Sciences launched the Apex Lecture Series in 2023. This school-wide seminar series brings scientists who are influencing the trajectory of their fields to engage with our scientific community on campus.
Lecture abstract
STING is a critical innate immunity adaptor protein in the cytosolic DNA-sensing pathway. Activation of STING by the second messenger cGAMP triggers a host of immune responses, including interferon production, autophagy, and inflammation. STING-mediated immunity is not only essential for responses to bacterial and viral infection, but also plays an important role in tumor suppression. STING therefore has been extensively studied and exploited for therapeutic purposes. In this seminar, I will present our recent cryo-EM structures of STING in various states and STING bound to several small, drug-like molecules that have potential to be developed into therapeutics. The structural analyses provide key insights into the fundamental regulatory mechanisms of STING and guide drug development.