The 2.0-angstrom resolution crystal structure of a trimeric antibody fragment with noncognate V-H-V-L domain pairs shows are arrangement of V-H CDR3

被引:70
作者
Pei, XY
Holliger, P
Murzin, AG
Williams, RL
机构
[1] UNIV CAMBRIDGE,CTR MRC,CTR PROT ENGN,CAMBRIDGE CB2 2QH,ENGLAND
[2] UNIV CAMBRIDGE,CTR MRC,MOL BIOL LAB,CAMBRIDGE CB2 2QH,ENGLAND
基金
英国医学研究理事会;
关键词
D O I
10.1073/pnas.94.18.9637
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The 2.0-Angstrom resolution x-ray crystal structure of a novel trimeric antibody fragment, a ''triabody,'' has been determined. The trimer is made up of polypeptides constructed in a manner identical to that previously described for some ''diabodies'': a V-L domain directly fused to the C terminus of a V-H domain-i.e., without any linker sequence. The trimer has three Fv heads with the polypeptides arranged in a cyclic, head-to-tail fashion. For the particular structure reported here, the polypeptide was constructed with a V-H domain from one antibody fused to the V-L domain from an unrelated antibody giving rise to ''combinatorial'' Fvs upon formation of the trimer. The structure shows that the exchange of the V-L domain from antibody B1-8, a V-lambda domain, with the V-L domain from antibody NQ11, a V-kappa domain, leads to a dramatic conformational change in the V-H CDR3 loop of antibody B1-8, The magnitude of this change is similar to the largest of the conformational changes observed in antibody fragments in response to antigen binding. Combinatorial pairing of V-H and V-L domains constitutes a major component of antibody diversity, Conformationally flexible antigen-binding sites capable of adapting to the specific CDR3 loop context created upon V-H-V-L pairing may be employed by the immune system to maximize the structural diversity of the immune response.
引用
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页码:9637 / 9642
页数:6
相关论文
共 40 条
  • [1] [Anonymous], ACTA CRYSTALLOGR D
  • [2] 3D DOMAIN SWAPPING - A MECHANISM FOR OLIGOMER ASSEMBLY
    BENNETT, MJ
    SCHLUNEGGER, MP
    EISENBERG, D
    [J]. PROTEIN SCIENCE, 1995, 4 (12) : 2455 - 2468
  • [3] HEAVY-CHAIN VARIABLE REGION CONTRIBUTION TO THE NPB FAMILY OF ANTIBODIES - SOMATIC MUTATION EVIDENT IN A GAMMA-2A VARIABLE REGION
    BOTHWELL, ALM
    PASKIND, M
    RETH, M
    IMANISHIKARI, T
    RAJEWSKY, K
    BALTIMORE, D
    [J]. CELL, 1981, 24 (03) : 625 - 637
  • [4] Crystal structure of the complex of the variable domain of antibody D1.3 and turkey egg white lysozyme: A novel conformational change in antibody CDR-L3 selects for antigen
    Braden, BC
    Fields, BA
    Ysern, X
    Goldbaum, FA
    DallAcqua, W
    Schwarz, FP
    Poljak, RJ
    Mariuzza, RA
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1996, 257 (05) : 889 - 894
  • [5] STRUCTURAL FEATURES OF THE REACTIONS - BETWEEN ANTIBODIES AND PROTEIN ANTIGENS
    BRADEN, BC
    POLJAK, RJ
    [J]. FASEB JOURNAL, 1995, 9 (01) : 9 - 16
  • [6] BRUNGER A, 1992, XPLOR MANUAL
  • [7] Immunoglobulin heavy chain gene replacement: A mechanism of receptor editing
    Chen, C
    Nagy, Z
    Prak, EL
    Weigert, M
    [J]. IMMUNITY, 1995, 3 (06) : 747 - 755
  • [8] CANONICAL STRUCTURES FOR THE HYPERVARIABLE REGIONS OF IMMUNOGLOBULINS
    CHOTHIA, C
    LESK, AM
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1987, 196 (04) : 901 - 917
  • [9] CONFORMATIONS OF IMMUNOGLOBULIN HYPERVARIABLE REGIONS
    CHOTHIA, C
    LESK, AM
    TRAMONTANO, A
    LEVITT, M
    SMITHGILL, SJ
    AIR, G
    SHERIFF, S
    PADLAN, EA
    DAVIES, D
    TULIP, WR
    COLMAN, PM
    SPINELLI, S
    ALZARI, PM
    POLJAK, RJ
    [J]. NATURE, 1989, 342 (6252) : 877 - 883
  • [10] DOMAIN ASSOCIATION IN IMMUNOGLOBULIN MOLECULES - THE PACKING OF VARIABLE DOMAINS
    CHOTHIA, C
    NOVOTNY, J
    BRUCCOLERI, R
    KARPLUS, M
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1985, 186 (03) : 651 - 663