Research
Interests
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Antigen presentation differences between protective MHCs versus non-protective MHCs by using HIV-1 model.
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Molecular basis of TCR cross recognition in host control of viral infection.
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T cell-based vaccine design.
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Structural insight into broadly neutralizing antibody recognition against viral glycosylated proteins.
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Small molecule compound or peptide targeting proteins located on cell surface or in cytoplasm.
Selected Published stories
Small molecule interaction with protein
Li X. et al. Nat Chem Biol., 2015 (PDB: 4O33 and 4O3E)
We discovered that terazosin (TZ), a widely marketed alpha1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline's ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1.
TCR beta selection in T cell development
Li X. et al. Science, 2020 (PDB: 6WL2, 6WL3, and 6WL4)
Self-discrimination, a critical but ill-defined molecular process programmed during thymocyte development, requires myriad pre-T cell receptors (preTCRs) and αβTCRs. Using X-ray crystallography, we show how a preTCR applies the concave β-sheet surface of its single variable domain (Vβ) to “horizontally” grab the protruding MHC α2-helix. By contrast, αβTCRs purpose all six complementary-determining region (CDR) loops of their paired VαVβ module to recognize peptides bound to MHC molecules (pMHCs) in “vertical” head-to-head binding. The preTCR topological fit ensures that CDR3β reaches the peptide’s featured C-terminal segment for pMHC sampling, establishing the subsequent αβTCR canonical docking mode. “Horizontal” docking precludes germline CDR1β– and CDR2β–MHC binding to broaden β-chain repertoire diversification before αβTCR-mediated selection refinement. Thus, one subunit successively attunes the recognition logic of related multicomponent receptors.
Molecular basis of HIV immune escape from CTLs
Li, X., et al. Cell Mol Immunol, 2017 (PDB: 5V5L)
Through structural analysis of the immunodominant HIV Gag epitope TW10 (TSTLQEQIGW, Gag residues 240-249), presented by HLA-B*5801, derived from patients bearing the potentially HIV-1-protective HLA class I allele B*5801, we found that the N-terminal residue of this antigenic peptide is not embedded in the HLA peptide-binding groove but instead unexpectedly extends out of the groove in an unconventional fashion. This observation contrasts with what occurs for the mutated TW10-T3N which binds the same HLA-B*5801 in a canonical fashion, as reported in the field. This structure reveals a previously unknown flexibility in the MHC presentation of antigenic peptides.
Signaling initiation of Kinase
Xu S., Li X. et al. Cell Discov., 2018
The focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK) purified in solution has two status. The gel filtration shows the majority is FAT monomer, while there is still relative fractions of dimer. Crystallographic structure displays the dimerization of FAT was formed by swapping one helic. This dimerization might play critical role in the FAK signaling initiation, and provide a potential target site for drug design.