Yong Xiong Ph.D. Assistant Professor Department of Molecular Biophysics & Biochemistry Center for Structural Biology Yale University 260 Whitney Avenue, JWG 423A New Haven, CT 06520-8114 Phone:  (203) 436-2608 FAX:  (203) 432-1296 Email:   yong.xiong@yale.edu

Innate immune responses to HIV infection
The first line of defense:
When HIV enters a cell, it encounters an antiviral DNA cytidine deaminase, APOBEC3G, which induces extensive mutations in the viral DNA that render the virus non-infectious. To elude the host defense system, HIV expresses the virion infectivity factor, Vif, which binds APOBEC3G and targets it for destruction by the proteasome.
      Our goal is to establish the chemical and structural principles by which APOBEC3G deaminates the viral DNA and the mechanisms by which Vif sequesters APOBEC3G. These objectives will be achieved through an integrated approach that combines data on the kinetics of the enzymatic reaction, biophysical characterization of the proteins and their interactions, and atomic resolution structures of the proteins in complex with key substrates and cofactors.
     Information gained from these studies will be used to direct structure-based design of anti-HIV drugs that act by inhibiting the action of Vif. Screening of these inhibitors will be carried out at Yale Chemical Genomics Screening Facility.
The cross-species barrier:
Retroviruses are often limited to a small number of host organisms due to species-specific cellular restriction factors. The tripartite motif protein TRIM5α is an important component of the cross-species barrier to HIV and many other retroviruses. TRIM5α inhibits retrovirus infection likely through interactions with the viral capsid protein (CA). The goal of this project is to characterize the TRIM5α-CA interaction in vitro and establish the structural basis for this interaction.

Structural insight of fatty acid synthesis
Fatty acid synthase (FAS) catalyzes cycles of multi-step reactions leading to the de novo synthesis of saturated fatty acids. In yeast this task is accomplished by a 2.6 Megadalton FAS complex that contains six copies of eight reaction centers. We have determined the crystal structure of yeast FAS, which illuminates how this multienzyme complex is initially activated and then carries out multiple steps of synthesis in each of six sterically isolated reaction chambers. Different reaction states will be examined to understand the mechanisms of fatty acid synthesis. Information gained will be used to design FAS inhibitors that might lead to antifungal and obesity therapeutics.

X-ray crystallography at low resolution
Electron microscopy (EM) to 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 de-blurring:
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.
Atomic models at very low resolution:
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.
 

Publications

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