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differences between human leukocyte antigen (HLA) molecules affect the specificity and conformation of their bound peptides and lead to differential selection of the T-cell repertoire. Mismatching during allogeneic transplantation can, therefore, lead to immunological reactions.<h4>Design and methods</h4>We investigated the structure-function relationships of six members of the HLA-B*41 allelic group that differ by six polymorphic amino acids, including positions 80, 95, 97 and 114 within the antigen-binding cleft. Peptide-binding motifs for B*41:01, *41:02, *41:03, *41:04, *41:05 and *41:06 were determined by sequencing self-peptides from recombinant B*41 molecules by electrospray ionization tandem mass spectrometry. The crystal structures of HLA-B*41:03 bound to a natural 16-mer self-ligand (AEMYGSVTEHPSPSPL) and HLA-B*41:04 bound to a natural 11-mer self-ligand (HEEAVSVDRVL) were solved.<h4>Results</h4>Peptide analysis revealed that all B*41 alleles have an identical anchor motif at peptide position 2 (glutamic acid), but differ in their choice of C-terminal p\u03a9 anchor (proline, valine, leucine). Additionally, B*41:04 displayed a greater preference for long peptides (>10 residues) when compared to the other B*41 allomorphs, while the longest peptide to be eluted from the allelic group (a 16mer) was obtained from B*41:03. The crystal structures of HLA-B*41:03 and HLA-B*41:04 revealed that both alleles interact in a highly conserved manner with the terminal regions of their respective ligands, while micropolymorphism-induced changes in the steric and electrostatic properties of the antigen-binding cleft account for differences in peptide repertoire and auxiliary anchoring.<h4>Conclusions</h4>Differences in peptide repertoire, and peptide length specificity reflect the significant functional evolution of these closely related allotypes and signal their importance in allogeneic transplantation, especially B*41:03 and B*41:04, which accommodate longer peptides, creating structurally distinct peptide-HLA complexes.","bibjson":{"author":[{"initials":"C","lastname":"Bade-D\ufffd\ufffdding","name":"Bade-D\ufffd\ufffdding C"},{"initials":"A","lastname":"Theodossis","name":"Theodossis A"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"L","lastname":"Kjer-Nielsen","name":"Kjer-Nielsen L"},{"initials":"B","lastname":"Eiz-Vesper","name":"Eiz-Vesper B"},{"initials":"A","lastname":"Seltsam","name":"Seltsam A"},{"initials":"T","lastname":"Huyton","name":"Huyton T"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"J","lastname":"McCluskey","name":"McCluskey J"},{"initials":"R","lastname":"Blasczyk","name":"Blasczyk R"}],"identifier":[{"id":"10.3324/haematol.2010.030924","type":"doi"},{"id":"20934997","type":"pubmed"}],"issue":["1"],"journal":{"iso_abbreviation":"Haematologica","name":""},"pages":["110-8"],"title":"The impact of human leukocyte antigen (HLA) micropolymorphism on ligand specificity within the HLA-B*41 allotypic family.","type":"article","url":"http://www.haematologica.org/cgi/doi/10.3324/haematol.2010.030924","volume":["96"],"year":[2011]},"in_pmc":"Y","in_pmce":"Y","open_access":"N"},"resolution":"1.30","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/3ln4"},"rcsb":{"url":"https://www.rcsb.org/structure/3ln4"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-B*41:03 binding \"AEMYGSVTEHPSPSPL\" at 1.30&#8491; resolution","unique_chain_count":3}}