This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. T-cell antigens presented by the CD1a antigen-presenting protein isolated from Mycobacterium tuberculosis have been studied to determine their structures and requirements for their antigenic presentation by CD1a. BUSM MS Resource efforts included ESI MS and MS/MS and GC/EI MS experiments and data interpretation. The series were found to be lipopeptides, structurally related to the iron-binding mycobactins D. b. Moody et al, Science, 2004). These results defined a new class of CD1 ligands that may have anti-HIV activity. When the X-ray structures were completed they supported the proposed basis for the binding specificity that was built on correlations between the determined structures and observed activity. Structure analysis of CD1a co-crystallized with a synthetic mycobactin lipopeptide at 2.8 ? resolution revealed that the single alkyl chain is inserted deep within the A-prime pocket of the groove, whereas its two peptidic branches protrude along the F pocket to the outer, alpha-helical surface of CD1a for recognition by the TCR. Remarkably, the cyclised lysine branch of the peptide moiety lies in the shallow F-prime pocket in a conformation that closely mimics that of the alkyl chain in the CD1a-sulfatide structure. Thus, this structural study illustrated how a single chain lipid can be presented by CD1 and that the peptide moiety of the lipopeptide is recognized by the TCR in contrast to dual chain glycolipids where the carbohydrate head group, as well as portions of the second alkyl chain, provide the basis for TCR specificity. A recent commentary in Nature (DB Moody, Nature. 2007 Jul 5;448(7149):36-7) incorporated concepts developed in the collaborative project. Synthetic versions of the lipopeptide with different stereochemistries have been prepared and their activities have been determnined, showing clearly that the stereochemistry is important for activity. The manuscript describing these results was recently published. (DC Young et al., Synthesis of dideoxymycobactin antigens presented by CD1a reveals T cell fine specificity for natural lipopeptide structures. J Biol Chem. 2009, 284, 25087-25096.)
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