Pymm, PhillipIlling, PatriciaRamarathinam, SriO'Connor, Geraldine M.Hughes, Victoria A.Hitchen, CorinnePrice, David A.Ho, BoscoMcVicar, Daniel W.Brooks, Andrew G.Purcell, Anthony W.Rossjohn, JamieVivian, Julian P.2017-03-312017-03-312017-02-20Pymm, P., Illing, P. T., Ramarathinam, S. H., O'Connor, G. M., Hughes, V. A., Hitchen, C.,... Vivian, J. P. (2017). MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. Nature Structural & Molecular Biology, 24, 387-394.1545-999310.1038/nsmb.3381http://hdl.handle.net/10034/620461This document is the Accepted Manuscript version of a published work that appeared in final form in Nature Structural & Molecular Biology. To access the final edited and published work see http://dx.doi.org/10.1038/nsmb.3381.Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems.enhttp://creativecommons.org/licenses/by-nc-nd/4.0/ImmunologyX-ray crystallographyHLAKIRArticle1545-9985Nature Structural & Molecular Biology