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Cited by 26vaccines and immunoinformatics approachesProtein Structure and DynamicsChemical Synthesis and Analysis

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HLA3DB: comprehensive annotation of peptide/HLA complexes enables blind structure prediction of T cell epitopes

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Gupta, Sagar, Nerli, Santrupti, Kutti Kandy, Sreeja, Mersky, Glenn L., Sgourakis, Nikolaos G.·2023·Nature Communications
DOI 10.1038/s41467-023-42163-zPMC PMC10564892

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Abstract

The class I proteins of the major histocompatibility complex (MHC-I) display epitopic peptides derived from endogenous proteins on the cell surface for immune surveillance. Accurate modeling of peptides bound to the human MHC, HLA, has been mired by conformational diversity of the central peptide residues, which are critical for recognition by T cell receptors. Here, analysis of X-ray crystal structures within our curated database (HLA3DB) shows that pHLA complexes encompassing multiple HLA allotypes present a discrete set of peptide backbone conformations. Leveraging these backbones, we employ a regression model trained on terms of a physically relevant energy function to develop a comparative modeling approach for nonamer pHLA structures named RepPred. Our method outperforms the top pHLA modeling approach by up to 19% in structural accuracy, and consistently predicts blind targets not included in our training set. Insights from our work may be applied towards predicting antigen immunogenicity, and receptor cross-reactivity.

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Metadata

Authors
Gupta, S., Nerli, S., Kutti Kandy, S., Mersky, G. L., & Sgourakis, N. G.
Affiliations
Children's Hospital of Philadelphia (US)
Corresponding author
Sgourakis, Nikolaos G.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-10-10
Volume
14
Issue
1
Pages
6349-6349
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-42163-z
PMC
PMC10564892
OpenAlex
W4387491415
Cited by
26
References
5
Citations by year
2026: 5 · 2025: 6 · 2024: 10 · 2023: 5
FWCI
2.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (5R35GM125034)
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases (5R01AI143997)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords
peptide-HLA complex, T cell epitopes, MHC class I, homology modeling, peptide backbone conformation, HLA allotypes, X-ray crystal structure, antigen immunogenicity, receptor cross-reactivity
MeSH terms
Histocompatibility Antigens, Humans, Peptides, Receptors, Antigen, T-Cell, Histocompatibility Antigens Class I, Epitopes, T-Lymphocyte

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