Binding interactions between peptides and proteins of the class II major histocompatibility complex.
The activation of helper T cells by peptides bound to proteins of the class II Major Histocompatibility Complex (MHC II) is pivotal to the initiation of an immune response. The primary functional requirement imposed on MHC II proteins is the ability to efficiently bind thousands of different peptides. Structurally, this is reflected in a unique architecture of binding interactions. The peptide is bound in an extended conformation within a groove on the membrane distal surface of the protein that is lined with several pockets that can accommodate peptide side-chains. Conserved MHC II protein residues also form hydrogen bonds along the length of the peptide main-chain. Here we review recent advances in the study of peptide-MHC II protein reactions that have led to an enhanced understanding of binding energetics. These results demonstrate that peptide-MHC II protein complexes achieve high affinity binding from the array of hydrogen bonds that are energetically segregated from the pocket interactions, which can then add to an intrinsic hydrogen bond-mediated affinity. Thus, MHC II proteins are unlike antibodies, which utilize cooperativity among binding interactions to achieve high affinity and specificity. The significance of these observations is discussed within the context of possible mechanisms for the HLA-DM protein that regulates peptide presentation in vivo and the design of non-peptide molecules that can bind MHC II proteins and act as vaccines or immune modulators.
McFarland
Benjamin J
BJ
Program in Biomolecular Structure and Design, Department of Chemistry, University of Washington, Box 351700, Seattle, Washington 98195-1700.
Beeson
Craig
C
D000818:Animals; D006681:HLA-D Antigens / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D010455:Peptides / Q000378:metabolism*; D013816:Thermodynamics
D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D010455:Peptides