Yong Xiong PhD

Associate Professor of Molecular Biophysics and Biochemistry

Research Interests

Innate immune systems; HIV; fatty acid synthase (FAS); polyketide synthase (PKS); Viral vectors


Research Summary

Our lab uses structural biology methods to study biological systems that have direct health impacts. A primary interest is innate immune systems, in particular, host cellular factors that fight viral infections such as those in the human body’s first line of defense against HIV. Another major interest is the mechanisms of fatty acid synthase (FAS), the cellular fat factory, and its close relationship to polyketide synthase (PKS), the cellular machinery that produces the most important natural products widely used in human medicine. Our goal is to provide a structural basis for understanding these systems and use the information gained to direct structure-based drug design of anti-viral, anti-fungal, and antibiotic compounds. Screening of inhibitors will be carried out at the Yale Chemical Genomics Screening Facility. Additionally, we are interested in the development of X-ray crystallographic methods that will push the limits of this technique.

Extensive Research Description

Our laboratory studies innate immune responses to viral infections and mechanisms of fatty acid synthesis. We use a variety of techniques, including X-ray crystallography, biochemistry, molecular biology, and computational biology. We also develop new X-ray crystallographic methods to facilitate the structural work.

Innate immune responses to HIV infection and viral countermeasures
APOBEC3 proteins. The innate immune system is the body's first line of defense against viral infections. Human antiviral protein APOBEC3G induces extensive mutations in HIV DNA that render the virus non-infectious. To evade the host defense system, HIV expresses the virion infectivity factor, Vif, which causes the degradation of APOBEC3G. We aim to establish the chemical and structural principles by which APOBEC3G mutates HIV DNA and the mechanisms by which HIV Vif sequesters APOBEC3G. Information gained from these studies will be used to direct structure-based design of Vif inhibitors that may lead to new anti-HIV drugs.
TRIM5a. Species-specific restriction factors can limit the number of host organisms that retroviruses are able to infect. The tripartite motif protein, TRIM5a, is an important component of the cross-species barrier to HIV and many other retroviruses. TRIM5a likely inhibits retrovirus infection through interactions with the viral capsid protein (CA). The goal of this project is to characterize the TRIM5a-CA interaction in vitro and establish the structural basis for this interaction.

Fatty acid synthesis
De novo synthesis of saturated fatty acids is catalyzed by fatty acid synthase (FAS) through multiple cycles of multi-step reactions. In yeast production of fatty acids is carried out by a 2.6 Megadalton FAS complex that contains 48 reaction centers. We have determined the crystal structure of the yeast FAS in the absence of any substrates. Additional reaction states will be examined to understand the mechanisms of fatty acid synthesis. Information gained can then be used to design FAS inhibitors that may lead to antifungal and obesity therapeutics.

X-ray crystallography at low resolutions
Electron microscope (EM) and X-ray crystallography. X-ray structure determination can utilize a low-resolution EM image for molecular replacement solution followed by phase extension to higher resolution by density modification.
Electron density deblurring. The electron density map obtained by X-ray crystallography or EM is often blurred due to motion and disorder in the crystal. We study the decoupling of the displacement by data sharpening techniques that treat individual domains of the molecule separately.
Folding calculation using X-ray data. Very low-resolution electron density maps (6-8 Å) can be used as a restraint for folding software in de novo calculations of atomic models.



Selected Publications

  • 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.
  • Randau, L*†, Stanley, B*, Kohlway, A., Mechta, S., Xiong, Y.† and Söll, D.† (2009) A cytidine deaminase edits tRNAs in archaea. Science 324, 657-659. (*: Equal contributions; †: Corresponding authors).
  • *Lomakin, I.B.,*#Xiong, Y., and #Steitz, T.A. (2007). The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together. Cell 129:319-332. (*equal contributions #corresponding authors).
  • Xiong, Y. and Steitz, T.A. (2004). Mechanism of transfer RNA maturation by CCA-adding enzyme without using an oligonucleotide template. Nature 430:640-645.
  • Li, W., Kamtekar, S., Xiong, Y., Grindley, N.D. and Steitz, T.A. Structure of a synaptic ?d resolvase tetramer covalently linked to two cleaved DNAs. Science 309, 1210-1215 (2005)

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