Crystal structures of HLA-A*0201 complexed with Melan-A/MART-1(26(27L)-35) peptidomimetics reveal conformational heterogeneity and highlight degeneracy of T cell recognition.
There is growing interest in using tumor associated antigens presented by class I major histocompatibility complex (MHC-I) proteins as cancer vaccines. As native peptides are poorly stable in biological fluids, researchers have sought to engineer synthetic peptidomimetics with greater biostability. Here, we demonstrate that antigenic peptidomimetics of the Melan-A/MART-1(26(27L)-35) melanoma antigen adopt strikingly different conformations when bound to MHC-I, highlighting the degeneracy of T cell recognition and revealing the challenges associated with mimicking native peptide conformation.
Douat-Casassus
Céline
C
Institut des Sciences Moléculaires (UMR-CNRS 5255) and Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux, 2 Rue Robert Escarpit, 33607 Pessac, France.
Borbulevych
Oleg
O
Tarbe
Marion
M
Gervois
Nadine
N
Jotereau
Francine
F
Baker
Brian M
BM
Quideau
Stéphane
S
D000951:Antigens, Neoplasm / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015234:HLA-A Antigens / Q000737:chemistry*; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009363:Neoplasm Proteins / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):22-5
20057045
J Struct Biol. 1999 Apr-May;125(2-3):156-65
10222271
Immunity. 2009 Dec 18;31(6):897-908
20064448
J Mol Biol. 2005 Oct 28;353(3):556-73
16197958
J Exp Med. 1999 Sep 6;190(5):705-15
10477554
Acta Crystallogr D Biol Crystallogr. 1997 Jul 1;53(Pt 4):448-55
15299911
J Immunol. 2001 Sep 15;167(6):3276-84
11544315
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
15572765
Melanoma Res. 2004 Aug;14(4):257-62
15305155
Annu Rev Immunol. 1999;17:369-97
10358763
Nat Rev Drug Discov. 2007 May;6(5):404-14
17473845
J Mol Biol. 2006 Oct 13;363(1):228-43
16962135
J Biol Chem. 2004 Jul 9;279(28):29175-84
15131131
Annu Rev Immunol. 1995;13:587-622
7612235
J Immunol. 2001 Nov 15;167(10):5852-61
11698460
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
15299926
J Mol Biol. 2007 Oct 5;372(5):1123-36
17719062
Science. 1994 Jul 15;265(5170):398-402
8023162
Annu Rev Immunol. 1993;11:213-44
8476560
Annu Rev Cell Dev Biol. 2008;24:343-68
18729726
Methods Enzymol. 1997;276:307-26
27754618
J Med Chem. 2007 Apr 5;50(7):1598-609
17328535
Immunity. 2009 Dec 18;31(6):885-96
20064447
Biochem J. 2008 Oct 15;415(2):183-96
18800968
J Immunol. 1998 Feb 15;160(4):1750-8
9469433
J Biol Chem. 2009 Oct 2;284(40):27281-9
19605354
Int J Cancer. 2009 Jan 1;124(1):130-9
18839429
Curr Opin Immunol. 2002 Feb;14(1):52-65
11790533
J Mol Biol. 2005 Feb 18;346(2):533-50
15670602
J Pept Sci. 2001 Mar;7(3):157-65
11297352