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Document Page 446 competition studies, murine IFN-γ N-terminal peptide consisting of residues 1–39 [IFN-γ (1–39)] blocked both binding to receptor and antiviral activity of IFN-γ [30]. Overlapping peptides of other regions of the IFN-γ molecule failed to block binding and function of IFN-γ [31]. Thus the combination of peptide mapping of epitope specificities and receptor competition using peptides has identified the Nterminus as a structurally and functionally important region of the IFN-γ molecule. This region is highlighted in the sequence of human IFN-γ found in Table 3. Interestingly, site-specific antibodies to the C-terminus of murine IFN-γ, which were induced using the peptide consisting of residues 95–133 [IFN-γ (95–133)], also neutralized IFN-γ activity, however IFN-γ (95–133) failed to block binding of IFN-γ to receptor and IFN-γ activity simultaneously. Antibodies to internal peptides failed to block both antiviral activity and binding of IFN-γ to receptor. In studies with recombinant murine IFN-γ receptor, which consisted of the entire α chain except for the transmembrane domain, the C-terminal peptide did block binding of IFN-γ to receptor [32]. Thus we have the interesting paradox wherein the IFN-γ C-terminal peptide blocked binding of IFN-γ to the recombinant, soluble receptor and yet did not block binding to the cell-surface receptor. One interpretation of these findings has allowed us to formulate the “velcro-key” model of binding to receptor that involves both N- and Cterminal domains of IFN-γ (Figure 5). The N-terminus binds in the “lock and key” manner characterized <strong>by</strong> specific ligand-receptor binding. The hydrophilic C-terminus binds to a region of the receptor distinct from that for the N-terminus, most likely through its polycationic region, which is conserved across species barriers. Binding of this type would exhibit high affinity and low specificity, similar to a piece of velcro. The C-terminal peptide of IFN-γ would therefore act as a poor competitor for cell-surface binding due to its low specificity alone. This interaction becomes specific in the context of the whole IFN-γ molecule and may increase the affinity of receptor binding. An alternative explanation that may also account for the inability of the C-terminal peptide to compete for cell-surface interactions is that its binding site is located not on the extracellular domain of the receptor, but rather on the intracellular domain. The primary differences between the cell-surface form of the IFN-γ receptor and (2) the accessibility of the recombinant receptor's cytoplasmic domain. A synthetic peptide corresponding to the membrane proximal region of the cytoplasmic domain of the murine IFN-γ receptor was able to bind IFN-γ and specifically compete with the binding of IFN-γ (95–133) to fixed/permeabilized cells [33]. Studies <strong>by</strong> others have reaffirmed the importance of both the N- and C-terminal regions of IFN-γ in function. Using recombinant DNA techniques, it has been shown that deletion of residues from the Nterminus of the molecule http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_446.html [4/9/2004 12:11:32 AM]
Document Figure 5 Velcro-key model of IFN-γ binding to its receptor. (From Reference 25. Copyright 1992. The American Association of Immunologists.) Page 447 results in decreased receptor binding [34]. Deletions or substitutions at the C- terminus have a direct effect on function of the molecule [35–38]. Epitope mapping of neutralizing monoclonal antibodies has also revealed an internal region of the molecule (from residues 84–94) as being functionally important [39]. This sequence bears strong homology to the nuclear localization sequence (NLS) of the SV40 large T antigen and has recently been demonstrated to be fully functional as an NLS for IFN-γ [40]. Thus, internal regions of the IFN-γ molecule are also likely to play an important functional role. B. IFN-γ Receptor α Chain Sites of Interaction with IFN-γ Both the human and the murine IFN-γ receptors consist of a ligand-binding subunit and a speciesspecific cofactor molecule. It is through interaction with this cell-surface receptor complex that IFN-γ exerts its biological effects. The IFN-γ molecule and its N-terminal peptide IFN-γ (1–39) bind specifically to the http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_447.html (1 of 2) [4/9/2004 12:11:36 AM]
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Structure-based Drug Design 14 Stru
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Document 2 Structural Studies of HI
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Document Table 3 HIV-1 RT Amino Aci
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Page 541 and 542: Document 17 Structure and Functiona
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Document D ddI, 152 tumour necrosis
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