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Document indicates that Cys116 in IL-1Ra is in a homologous position with Phe117 in IL- 1β. The K145D + Y147T analog lost all detectabled activity (both binding and bioactivity), whereas the Y147G analog lost all bioactivity but retained 100% binding. These data suggest that Tyr147 is important for bioactivity of IL-1Ra K145D. C. Insertion of β Bulge Page 415 A region of charged amino acids (Gln48 to Asn53, a β bulge) positioned between β strands 4 and 5 has been implicated in IL-1β binding to its receptor and its immunostimulatory properties [42, 64–67]. The β-bulge residues form a protrusion on the edge of the open end of the β barrel. Evidence for this patch of amino acids involved in the function of this molecule comes from mutagenesis studies in which deletions or substitutions of residues in this region reduced IL- 1β agonist activity without affecting receptor binding [62,63]. Simoncsits et al. have shown that deletion of amino acids 52–54 (SND) in IL- 1β reduces IL-1RI binding by 10 fold and biological activity by 1000 fold [63]. Also, studies indicate that a synthetic peptide derived from IL-1β (VQGEESNDK), which contains these six β bulge amino acids, has immunostimulatory but no inflammatory effects normally associated with IL-1 [64–66]. The insertion of VQGEESNDK into recombinant human ferritin H chain and recombinant flagellin from Salmonella muenchen increased the immunogenicity of these antigens in mice [67]. Greenfeder et al. inserted this β-bulge region into IL-1Ra K145D either after Ile51 of after Pro53 [61]. The insertion of the β bulge (QGEESN) after either position 51 or 53 of IL-1Ra K145D resulted in analogs that retained full IL-1RI binding and increased bioactivity by 3–4 fold. Aslo they tried to obtain the analogs of the QGEESN insertion in the absence of the K145D mutation either after amino acid 51 or 53 of IL-1Ra. None of the plasmid clones with the insertion at position 51 of IL-1Ra produced the appropriate protein, whereas they were able to isolate clones with the insertion at position 53. Based on these results, Greenfeder et al. suggest that in the first case the insertion interfered in the proper folding of the protein, whereas the second mutant folded properly and exhibited only 10 to 20% of the IL-1RI binding activity. The mutants with K145D + QGEESN insertion after Ile51 of IL-1Ra showed an increase in bioactivity in the range of 3–8 fold. The triple mutant IL-1Ra K145D/H54P/QGEESN showed a higher bioactivity, and based on their mutagenesis study, Greenfeder et al. suggest that this increase in activity may be due to the introduction of Pro and not the removal of His at position 54 in the K145D mutant of IL-1Ra. The cumulative effects of these three mutations are also interesting since their positions on the IL-1Ra protein appear to be spatially separated. The residues Ile51 and His54 are located on the open face of the β barrel of IL-1Ra, whereas Lys145 is located away from the open barrel end. In IL-1β, the same relative http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_415.html [4/5/2004 5:47:38 PM]
Document Page 416 positions of the β bulge and Asp145 are observed [42] with the two regions separated by the known IL- 1RI binding site. We have compiled the available site-directed mutants of IL-1β and sorted them according to the following four categories: (1) mutants that shows significantly higher agonistic activity, A1T, P2M, S5R, N89G, K92R, and K93R; (2) mutants that show significantly higher antagonistic activity, R4E, C8S, T9G, T9Q, T9E, L10T,C,S,A, C71X, R11G, K93M, M95R, E96Q, K103Q, and D145K;, (3) mutants that show significantly higher binding, A1T + P2M, S5R, T9L, T9W, P87S, P87H, K88V,G,L, N89R, E96Q, K103Q, G, C and M148A; and (4) mutants that show significantly lower binding, R4A,K,D, L6A, T9E, L10N,T,C,S,A, H30R, M44S, F46D, A, 156A, V58A, K92E, K93L,A,F,S,E,Q,L, K103S, and E105S,K. These four types of mutants are shown in Figure 11a–d. Taken together, this information supports our earlier proposal of the receptor-binding epitope. This was further characterized as functional sites A and B of interleukin-1. The first site, Area A is structurally conserved in all three molecules and contains residues Arg11, His30, and Asp145 in IL-1β Asn17, Ala36, and Asp147 in IL-1α; and Trp16, Tyr34, and Lys145 in IL-1Ra. Present in both active IL-1 molecules, Asp145 has been recognized as an important residue in IL-1 binding. Area B has also been identified in both IL-1α and IL-1β it contains a large hydrophilic ridge around solvent-accessible hydrophobic residues. In-IL-1β, this region contains the 7-residue hydrophilic ridge (Arg4, Gln48, Glu51, Asn53, Lys93, Glu105, Asn108) around 5 hydrophobic solvent-accessible residues (Leu6, Val47, Ile56, Leu110, Val151). Figure 12 shows a surface presentation of the proposed receptor-binding epitope. In IL-1α, the 7-residue hydrophilic ridge has been identified with residues (Arg12, Ile14, Asp60, Asp61, Ile64, Lys96, and Trp109, which when mutated resulted in significant loss of binding to the receptor. Area B is structurally conserved in IL-1β and in IL-1α, but is lacking in IL-1Ra. For this reason Area A has been proposed as the binding region while Area B has been proposed as the triggering region. D. Peptide Fragments Peptide-based IL-1 antagonists have been derived from the primary sequence of IL-1α or IL-1β. Stepwise synthesis of a series of peptides from amino-terminal to carboxy-terminal regions did not provide any satisfactory results [68]. Polypeptide fragments of IL-1β, termed somnogeneic peptides, induced sleep in mammals [69], 61.5% NREMS at a dose of 20 ng. The numbering of these peptides in proIL-1 are 178–207, 199–225, 208–240 and that of mature IL-1β are 62–91, 83–109, and 92–124 (seq 92–124=KKKMEKRFVFNKIENNKLEFESAQFPNWYIST). Monsanto company has identified a peptide fragment of IL-1β (41–70) exhibiting inhibitory effects for IL-1β and IL-1β, but not TNF-α, at 5 nM (5 ng/mL). Peptide 56–70 is a http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_416.html [4/5/2004 5:48:12 PM]
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Structure-based Drug Design 14 Stru
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Document Page 626 SJ, Ogden RC, Red
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Document 97; (e) Fujii I, Nakamura
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Document Med Biol 1991; 306:9-21; (
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Document Page 629 ML, Clare M, Decr
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Document Page 630 177. (a) Bode W,
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Document Page 631 197. Musil D, Zuc
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Document son AH, Drummond AH, Huxle
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Document 236. (a) Marshall MS. TIBS
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Document 274. (a) Kavanaugh WM, Wil
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Document replacements, 563-565 1-am
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Document inhibitor binding, 323, 33
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Document site, 52, 55, 61 triad, 24
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Document factors, 247 Combination t
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Document Cyclotheonamide A (CtA), 2
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document [Human immunodeficiency vi
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Document overview, 103-104, 108-109
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Document antagonistic activity, 416
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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