A MUTATIONAL ANALYSIS OF RECEPTOR-BINDING SITES OF INTERLEUKIN-1-BETA - DIFFERENCES IN BINDING OF HUMAN INTERLEUKIN-1-BETA MUTEINS TO HUMAN AND MOUSE RECEPTORS

被引:31
作者
GRUTTER, MG [1 ]
VANOOSTRUM, J [1 ]
PRIESTLE, JP [1 ]
EDELMANN, E [1 ]
JOSS, U [1 ]
FEIGE, U [1 ]
VOSBECK, K [1 ]
SCHMITZ, A [1 ]
机构
[1] CIBA GEIGY AG, DEPT INFLAMMAT BONE & ALLERGY, DIV PHARMACEUT, CH-4002 BASEL, SWITZERLAND
来源
PROTEIN ENGINEERING | 1994年 / 7卷 / 05期
关键词
INTERLEUKIN-1-BETA; MUTATIONAL MAPPING; RECEPTOR BINDING; SPECIES DIFFERENCE;
D O I
10.1093/protein/7.5.663
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The 3-D crystal structure of interleukin-1 beta (IL-1 beta) has been used to define its receptor binding surface by mutational analysis. The surface of IL-1 beta was probed by site-directed mutagenesis. A total of 27 different IL-1 beta muteins were constructed, purified and analyzed. Receptor binding measurements on mouse and human cell lines were performed to identify receptor affinities. IL-1 beta muteins with modified receptor affinity were evaluated for structural integrity by CD spectroscopy or X-ray crystallography. Changes in six surface loops, as well as in the C- and N-termini, yielded muteins with lower binding affinities. Two muteins with intact binding affinities showed 10- to 100-fold reduced biological activity. The surface region involved in receptor binding constitutes a discontinuous area of similar to 1000 Angstrom(2) formed by discontinuous polypeptide chain stretches. Based on these results, a subdivision into two distinct local areas is proposed. Differences in receptor binding affinities for human and mouse receptors have been observed for some muteins, but not for wild-type IL-1 beta. This is the first time a difference in binding affinity of IL-1 beta muteins to human and mouse receptors has been demonstrated.
引用
收藏
页码:663 / 671
页数:9
相关论文
共 50 条
  • [11] THE CELL-SURFACE RECEPTORS FOR INTERLEUKIN-1-ALPHA AND INTERLEUKIN-1-BETA ARE IDENTICAL
    DOWER, SK
    KRONHEIM, SR
    HOPP, TP
    CANTRELL, M
    DEELEY, M
    GILLIS, S
    HENNEY, CS
    URDAL, DL
    [J]. NATURE, 1986, 324 (6094) : 266 - 268
  • [12] COMPLETE RESONANCE ASSIGNMENT FOR THE POLYPEPTIDE BACKBONE OF INTERLEUKIN-1-BETA USING 3-DIMENSIONAL HETERONUCLEAR NMR-SPECTROSCOPY
    DRISCOLL, PC
    CLORE, GM
    MARION, D
    WINGFIELD, PT
    GRONENBORN, AM
    [J]. BIOCHEMISTRY, 1990, 29 (14) : 3542 - 3556
  • [13] PRIMARY STRUCTURE AND FUNCTIONAL EXPRESSION FROM COMPLEMENTARY-DNA OF A HUMAN INTERLEUKIN-1 RECEPTOR ANTAGONIST
    EISENBERG, SP
    EVANS, RJ
    AREND, WP
    VERDERBER, E
    BREWER, MT
    HANNUM, CH
    THOMPSON, RC
    [J]. NATURE, 1990, 343 (6256) : 341 - 346
  • [14] CRYSTAL-STRUCTURE OF RECOMBINANT HUMAN INTERLEUKIN-1-BETA AT 2.0-A RESOLUTION
    FINZEL, BC
    CLANCY, LL
    HOLLAND, DR
    MUCHMORE, SW
    WATENPAUGH, KD
    EINSPAHR, HM
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1989, 209 (04) : 779 - 791
  • [15] GEHRKE L, 1990, J BIOL CHEM, V265, P5922
  • [16] STRUCTURE OF INTERLEUKIN 1-ALPHA AT 2.7-A RESOLUTION
    GRAVES, BJ
    HATADA, MH
    HENDRICKSON, WA
    MILLER, JK
    MADISON, VS
    SATOW, Y
    [J]. BIOCHEMISTRY, 1990, 29 (11) : 2679 - 2684
  • [17] INTERLEUKIN-1 RECEPTOR ANTAGONIST ACTIVITY OF A HUMAN INTERLEUKIN-1 INHIBITOR
    HANNUM, CH
    WILCOX, CJ
    AREND, WP
    JOSLIN, FG
    DRIPPS, DJ
    HEIMDAL, PL
    ARMES, LG
    SOMMER, A
    EISENBERG, SP
    THOMPSON, RC
    [J]. NATURE, 1990, 343 (6256) : 336 - 340
  • [18] HENDRICKSON WA, 1980, COMPUTING CRYSTALLOG
  • [19] SITE-DIRECTED MUTAGENESIS BY OVERLAP EXTENSION USING THE POLYMERASE CHAIN-REACTION
    HO, SN
    HUNT, HD
    HORTON, RM
    PULLEN, JK
    PEASE, LR
    [J]. GENE, 1989, 77 (01) : 51 - 59
  • [20] MUTEINS OF HUMAN INTERLEUKIN-1 THAT SHOW ENHANCED BIOACTIVITIES
    HUANG, JJ
    NEWTON, RC
    HORUK, R
    MATTHEW, JB
    COVINGTON, M
    PEZZELLA, K
    LIN, Y
    [J]. FEBS LETTERS, 1987, 223 (02) : 294 - 298