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YONG XIONG
Our laboratory studies host immune responses to viral infections and the biosynthesis of medically important natural products by multi-enzyme complexes. We use a variety of techniques, including X-ray crystallography, electron microscopy, biochemistry, and computational biology. We also develop new structural biology methods.
Innate immune responses to viral infection:
The first line of defense:When HIV enters a cell, a host antiviral protein, APOBEC3G (A3G), induces extensive mutations in the viral DNA that render the virus non-infectious. To elude the host defense system, the HIV virion infectivity factor, Vif, binds A3G and targets it for destruction by the proteasome. Our goal is to establish the chemical and structural principles by which A3G deaminates the viral DNA and the mechanisms by which Vif sequesters A3G. Information gained will be used to direct structure-based design of anti-HIV drugs. Screening of Vif inhibitors is being carried out at the Yale Small Molecule Discovery Center.
The last line of defense: When the newly generated HIV virion is budding off the host cell, a host membrane protein, Tetherin, tethers the viral particle to the cellular membrane to prevent its release. Tetherin also has anitiviral activities against many other enveloped viruses. HIV has evolved to express the viral protein u, Vpu, to antagonize the Tetherin function. This newly discovered system has become a central focus of the HIV field. We aim to study the structure and function of the Tetherin-Vpu interactions.
Viral evasion of immune surveillance: The HIV protein Nef interacts with a diverse range of cellular factors to enhence viral fitness and dissemination. A major function of Nef is to enable viral evasion of host immune system by downregulating the Major Histocompatibility Complex Class I (MHC-I) and CD4 proteins. Nef mediates the association of MHC-I with the adaptor protein complex 1 (AP1) leading to the delivery of MHC-I to the endosome and lysosome via clathrin-coated vesicles. We aim to elucidate the structural and biochemical principles of how HIV Nef hijacks the cellular membrane trafficking machinery to sequester the host immune surveillance molecules.
Biosynthesis of polyketides and fatty acids:
Polyketides are one of the largest families of natural products and are among the most important microbial metabolites in human medicine. Polyketides are assembled from cellular acetyl and malonyl building blocks by polyketide synthases (PKS), which are large (1-10 MDa), multifunctional protein complexes. The PKS functions are closely related to those of the fatty acid synthase (FAS), with the major difference that the main carbon chains of fatty acids are fully reduced to alkyl chains, whereas the intermediates in polyketide biosynthesis may be only partially processed. We aim to establish a structural and biochemical framework of how these important, complex cellular machines function.
Atomic structure at low resolutions:
The limitation of low-resolution data has increasingly become the bottleneck of obtaining atomic structures, as structural biology now moves toward the “high-hanging fruits” such as macromolecular complexes. We aim to develop techniques that will expand the current capabilities of atomic structure determination at low resolution. By integrating X-ray crystallography, electron microscopy, and <em>de novo</em> folding calculations to overcome the obstacles to low-resolution structure determination, our efforts will extend the current scope of structural biology so that difficult and currently intractable structures can be determined routinely.
Selected publications:
Yang, H., Wang, J., Jia, X., Zang, T., McNatt, M.W., Pan. B., Meng W., Wang, H., Bieniasz, P.D. & Xiong, Y. (2010).
Structural Insight into the Mechanisms of Enveloped Viruses Tethering by Tetherin/BST2. Proc. Natl. Acad. Sci. USA. 107, 18428-18432.
Wolfe, L.S., Stanley, B.J., Liu, C., Eliason, W.K., & Xiong, Y. (2010). Dissection of HIV Vif interaction with the human E3 ubiquitin ligase. J Virol. 84, 7135-7139.
Fang, Y., Jayaram, H., Shane, T., Kolmakova-Partensky, L., Wu, F., Williams, C., Xiong. Y. & Miller. C. (2009). Structure of a Prokaryotic Virtual Proton Pump at 3.2 Å Resolution. Nature 460, 1040-1043.
Lomakin, I. B., Xiong, Y. and Steitz, T. A. The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together. Cell 129, 319-332 (2007)
Last updated 8/16/11 myc
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