Peptide and Peptide Mimetic Inhibitors of Antigen Presentation by HLA-DR Class II MHC Molecules. Design, Structure−Activity Relationships, and X-ray Crystal Structures

Bolin, David; Swain, Amy L.; Sarabu, Ramakanth; Berthel, Steven J.; Gillespie, Paul; Huby, Nicholas; Makofske, Raymond; Orzechowski, Lucja; Perrotta, A.; Toth, Katherine; Cooper, Joel P.; Jiang, Nan; Falcioni, Fiorenza; Campbell, Robert M.; Çox, Donald C.; Gaizband, Diana; Belunis, Charles; Vidovic, Damir; Ito, Kouichi; Crowther, R.; Kammlott, U.; Zhang, Xiaolei; Palermo, Robert E.; Weber, David V.; Guenot, Jeanmarie; Nagy, Zoltán Á.; Olson, Gary L.

doi:10.1021/jm000034h

Cited by 81 publications

(81 citation statements)

References 41 publications

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“…Our studies lead to the unexpected but compelling conclusion that, although each of the four residues studied do, in fact, contribute to peptide stability, those hydrogen bonds localized to the amino terminus of the peptide contribute profoundly and disproportionately to the stability of peptide⅐class II interactions. This conclusion is consistent with observations made with DR molecules, using chemical modifications of the peptide to assess the contribution of hydrogen bonds in peptide⅐class II stability (22) and with conformational analyses showing that formation of the peptide amino-terminal backbone hydrogen bonds is critical to the nucleation of a mature MHC protein conformation (23).…”

Section: Discussionsupporting

confidence: 90%

Energetic asymmetry among hydrogen bonds in MHC class II⋅peptide complexes

McFarland

Katz

Beeson

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Comparison of crystallized MHC class II⅐peptide complexes has revealed that, in addition to pocket interactions involving the peptide side chains, peptide binding to MHC class II molecules is characterized by a series of hydrogen bonds between genetically conserved amino acid residues in the class II molecule and the main chain of the peptide. Many class II⅐peptide structures have two sets of symmetrical hydrogen bonds at the opposite ends of the class II antigen-binding groove (␤-His-81, ␤-Asn-82 vs. ␣-His-68, ␣-Asn-69). In this study, we alter these peripheral hydrogen bonds and measure the apparent contribution of each to the kinetic stability of peptide⅐class II complexes. Single conservative amino substitutions were made in the I-A d protein to eliminate participation as a hydrogen bonding residue, and the kinetic stability of a diverse set of peptides bound to the substituted I-A d proteins was measured. Although each hydrogen bond does contribute to peptide binding, our results point to the striking conclusion that those hydrogen bonds localized to the amino terminus of the peptide contribute profoundly and disproportionately to the stability of peptide interactions with I-A d . We suggest that the peripheral hydrogen bonds at the amino terminus of the bound peptide that are conserved in all class II⅐peptide crystal structures solved thus far form a cooperative network that critically regulates peptide dissociation from the class II molecule.M ajor histocompatibility complex (MHC) class II molecules are composed of two noncovalently associated, polymorphic transmembrane proteins, termed ␣ and ␤, of approximate molecular mass of 33 kDa and 28 kDa, respectively. They interact with T cell receptors to provoke an antigen-specific CD4 ϩ T cell response. Crystal structures of class II molecules have provided insight into the structural elements that control interactions with peptide. Both polymorphic and genetically conserved amino acid residues make contacts with the bound peptide (1-7). Most of the polymorphic residues face the interior of the peptide-binding groove, and thus contribute to allele-dependent peptide binding. Similar to what has been observed in class I molecules, MHC class II molecules appear to have ''pockets'' that are capable of binding to peptide side chains. In addition to these pocket interactions, MHC class II molecules bind peptide through a series of hydrogen bonds between genetically conserved amino acid residues in the class II molecule and the main chain of the peptide. These conserved residues bind at relatively regular intervals throughout the length of the peptide, and apparently stabilize the peptide in a fairly fixed polyproline type II conformation throughout the length of the peptide-binding pocket (3).One striking aspect of class II⅐peptide structures noted in murine complexes (6, 7) are two sets of symmetrical hydrogen bonds at the opposite ends of the binding pocket (Fig. 1). The hydrogen bonds contributed by ␤-His-81 and ␤-Asn-82 are localized to the bound peptide's amino...

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Section: Discussionsupporting

confidence: 90%

Energetic asymmetry among hydrogen bonds in MHC class II⋅peptide complexes

McFarland

Katz

Beeson

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, these antibodies appear to be sensitive to conformational rearrangement(s) in this region, rather than to a simple steric block of key residues by peptide binding. This idea is supported by the loss of MEM recognition upon YRAL peptide binding, this peptide is likely to bind only in the P1-P4 region of the peptide binding site (56), far away from the DR1␤-(53-67) epitope, with a closest approach of ϳ9 Å (from the peptide COOH terminus to Trp-60). Some evidence for conformational lability in this region of HLA-DR1 can be seen in crystal structures of its peptide complexes, which exhibit significant peptide-to-peptide variation in this region, and relatively high thermal B-factors, particularly for residues 63-67.…”

Section: Discussionmentioning

confidence: 98%

Monoclonal Antibodies Specific for the Empty Conformation of HLA-DR1 Reveal Aspects of the Conformational Change Associated with Peptide Binding

Carven

Chitta

Hilgert

et al. 2004

Journal of Biological Chemistry

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Class II major histocompatibility complex (MHC) proteins bind peptides and present them at the cell surface for interaction with CD4؉ T cells as part of the system by which the immune system surveys the body for signs of infection. Peptide binding is known to induce conformational changes in class II MHC proteins on the basis of a variety of hydrodynamic and spectroscopic approaches, but the changes have not been clearly localized within the overall class II MHC structure. To map the peptideinduced conformational change for HLA-DR1, a common human class II MHC variant, we generated a series of monoclonal antibodies recognizing the ␤ subunit that are specific for the empty conformation. Each antibody reacted with the empty but not the peptide-loaded form, for both soluble recombinant protein and native protein expressed at the cell surface. Antibody binding epitopes were characterized using overlapping peptides and alanine scanning substitutions and were localized to two distinct regions of the protein. The pattern of key residues within the epitopes suggested that the two epitope regions undergo substantial conformational alteration during peptide binding. These results illuminate aspects of the structure of the empty forms and the nature of the peptide-induced conformational change. Major histocompatibility complex (MHC)1 molecules are heterodimeric cell-surface proteins that play an important role in the initiation of antigen-specific immune responses. Class II MHC proteins bind peptides derived from extracellular, endosomal, and internalized cell-surface antigens, and present them at the cell surface for inspection by CD4 ϩ T cells (1). Three-dimensional structures have been determined for peptide complexes of several polymorphic variants of both human and murine class II MHC molecules (reviewed in Ref.2). Both the MHC ␣ and ␤ chains contribute to the peptide binding site, which is made up of a ␤ sheet floor topped by two roughly parallel ␣ helical regions. Each subunit contributes an immunoglobulin-like domain below the peptide binding site, as well as short transmembrane and cytoplasmic domains. Peptides bind in an extended conformation in the groove between the two helices, with ϳ10 residues able to interact with the MHC protein, and the peptide termini extending from the binding site. This conformation, similar to a polyproline type II helix, has a 2.7-residue repeat and appears to be dictated by a network of conserved hydrogen bonding interactions between the MHC and bound peptide (3). The conformation places 4 -6 of the peptide side chains into pockets within the overall groove. The residues lining these pockets vary between allelic variants, providing different peptide-sequence binding specificity. Overall the interaction buries ϳ70% of the peptide surface area in the central region of a bound peptide, leaving the remainder available for interaction with antigen receptors on T cells (4).Although the canonical structure visualized by x-ray crystallography is relatively stereotyped, a number of studies h...

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“…In addition, methylated amino acids can be incorporated into an APL to protect it from degradation by CatB, CatD and CatH. The resulting APL inhibit T cell activation [113,114]. In addition to protease resistance being beneficial for effective APL, an improvement in APL uptake can potentially reduce the need for APL overload.…”

Section: Generation Of Protease-resistant Aplmentioning

confidence: 99%

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Burster

Boehm

2010

Diabetes Metabolism Res

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SummaryBoth CD4 + and CD8 + T lymphocytes play a crucial role in the autoimmune process leading to T1D. Dendritic cells take up foreign antigens and autoantigens; within their endocytic compartments, proteases degrade exogenous antigens for subsequent presentation to CD4 + T cells via MHC class II molecules. A detailed understanding of autoantigen processing and the identification of autoantigenic T cell epitopes are crucial for the development of antigen-based specific immunomodulators. APL are peptide analogues of auto-immunodominant T cell epitopes that bind to MHC class II molecules and can mediate T cell activation. However, APL can be rapidly degraded by proteases occurring in the extracellular space and inside cells, substantially weakening their efficiency. By contrast, protease-resistant APL function as specific immunomodulators and can be used at low doses to examine the functional plasticity of T cells and to potentially interfere with autoimmune responses. Here, we review the latest achievements in (pro)-insulin processing in the MHC class II pathway and the generation of APL to mitigate autoreactive T cells and to activate Treg cells.

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Peptide and Peptide Mimetic Inhibitors of Antigen Presentation by HLA-DR Class II MHC Molecules. Design, Structure−Activity Relationships, and X-ray Crystal Structures

Cited by 81 publications

References 41 publications

Energetic asymmetry among hydrogen bonds in MHC class II⋅peptide complexes

Energetic asymmetry among hydrogen bonds in MHC class II⋅peptide complexes

Monoclonal Antibodies Specific for the Empty Conformation of HLA-DR1 Reveal Aspects of the Conformational Change Associated with Peptide Binding

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

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