Abstract
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 sideโchains. Conserved MHC II protein residues also form hydrogen bonds along the length of the peptide mainโchain. Here we review recent advances in the study of peptideโMHC II protein reactions that have led to an enhanced understanding of binding energetics. These results demonstrate that peptideโMHC 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 bondโmediated 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 HLAโDM protein that regulates peptide presentation in vivo and the design of nonโpeptide molecules that can bind MHC II proteins and act as vaccines or immune modulators. ยฉ 2002 John Wiley & Sons, Inc. Med Res Rev, 22, No. 2, 168โ203, 2002; DOI 10.1002/med.10006