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Structure-based selection of human metabolite binding P4 pocket of DRB1*15:01 and DRB1*15:03, with implications for multiple sclerosis

Genes & Immunity volume 20, pages 46–55 (2019)Cite this article

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Abstract

Binding of small molecules in the human leukocyte antigen (HLA) peptide-binding groove may result in conformational changes of bound peptide and an altered immune response, but previous studies have not considered a potential role for endogenous metabolites. We performed virtual screening of the complete Human Metabolite Database (HMDB) for docking to the multiple sclerosis (MS) susceptible DRB1*15:01 allele and compared the results to the closely related yet non-susceptible DRB1*15:03 allele; and assessed the potential impact on binding of human myelin basic peptide (MBP). We observed higher energy scores for metabolite binding to DRB1*15:01 than DRB1*15:03. Structural comparison of docked metabolites with DRB1*15:01 and DRB1*15:03 complexed with MBP revealed that PhenylalanineMBP92 allows binding of metabolites in the P4 pocket of DRB1*15:01 but ValineMBP89 abrogates metabolite binding in the P1 pocket. We observed differences in the energy scores for binding of metabolites in the P4 pockets of DRB1*15:01 vs. DRB1*15:03 suggesting stronger binding to DRB1*15:01. Our study confirmed that specific, disease-associated human metabolites bind effectively with the most polymorphic P4 pocket of DRB1*15:01, the primary MS susceptible allele in most populations. Our results suggest that endogenous human metabolites bound in specific pockets of HLA may be immunomodulatory and implicated in autoimmune disease.

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Acknowledgements

This study was supported by grants from the National Institutes of Health (U19NS095774, R01AI128775). The authors wish to thank Professor Jorge Oksenberg for his support and valuable comments on this work.

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  1. Department of Neurology, University of California San Francisco, San Francisco, CA, 94158, USA

    Maneesh K. Misra, Vincent Damotte & Jill A. Hollenbach

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  1. Maneesh K. Misra
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Correspondence to Jill A. Hollenbach.

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Misra, M.K., Damotte, V. & Hollenbach, J.A. Structure-based selection of human metabolite binding P4 pocket of DRB1*15:01 and DRB1*15:03, with implications for multiple sclerosis. Genes Immun 20, 46–55 (2019). https://doi.org/10.1038/s41435-017-0009-5

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