Related Experiment Video

Updated: Aug 6, 2026

Using X-ray Crystallography, Biophysics, and Functional Assays to Determine the Mechanisms Governing T-cell Receptor Recognition of Cancer Antigens
09:53

Using X-ray Crystallography, Biophysics, and Functional Assays to Determine the Mechanisms Governing T-cell Receptor Recognition of Cancer Antigens

Published on: February 6, 2017

Phosphorylation of a Tumor-Derived ASXL2 Epitope Remodels the HLA-Bound Peptide Conformational Ensemble and

Jiahui Zhang1,2, Lin Lv1,2,3, Bairun Chen4

  • 1National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China.

Computational and Structural Biotechnology Journal
|July 24, 2026
PubMed

Insights

Phosphorylation of cancer epitopes alters peptide-HLA interactions and dynamics. This study reveals how phosphorylation and protonation impact binding, aiding the development of targeted cancer immunotherapies.

Area of Science:

  • Immunology
  • Structural Biology
  • Computational Biology

Background:

  • Cancer immunotherapy relies on identifying tumor-specific epitopes presented by human leukocyte antigen (HLA) class I molecules.
  • Posttranslational modifications, like phosphorylation, on these epitopes can indicate oncogenic signaling and serve as tumor-selective targets.
  • The precise structural and biophysical effects of phosphorylation on peptide-HLA complex conformation and interactions are not fully understood.

Purpose of the Study:

  • To investigate the structural and biophysical mechanisms by which phosphorylation affects peptide-HLA complexes.
  • To compare the effects of a phosphorylated peptide, its nonphosphorylated form, and its protonated-phosphorylated state on HLA binding.
  • To elucidate how these modifications influence the conformational ensemble and interaction networks within the peptide-HLA complex.

Main Methods:

  • All-atom molecular dynamics simulations of peptide-HLA complexes.
  • Analysis of a phosphorylated epitope derived from ASXL transcriptional regulator 2 (ASXL2).
  • Principal component analysis to assess conformational fluctuations and ensembles.

Main Results:

  • Phosphorylation reconfigures the noncovalent interaction network within the HLA binding groove by introducing new local contacts.
  • Phosphorylation restricts peptide conformational fluctuations, altering the overall conformational ensemble of the peptide-HLA complex.
  • Protonation of the phosphorylated peptide further remodels the interaction network and conformational ensemble.

Conclusions:

  • Phosphorylation significantly modulates the conformational ensemble and interaction network of peptide-HLA complexes.
  • These findings provide a structural and biophysical basis for understanding phosphorylation's role in peptide-HLA interactions.
  • This knowledge can aid in prioritizing cancer-specific targets for the development of novel immunotherapies.

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