Conformations of the third hypervariable region in the VH domain of immunoglobulins

被引:276
作者
Morea, V
Tramontano, A
Rustici, M
Chothia, C
Lesk, AM
机构
[1] Univ Cambridge, Ctr Mrc, Dept Haematol, Cambridge CB2 2QH, England
[2] MRC, Mol Biol Lab, Ctr Mrc, Cambridge CB2 2QH, England
[3] Univ Sassari, Dipartimento Chim, I-07100 Sassari, Italy
[4] Ist Ric Biol Mol P Angeletti, I-00045 Pomezia, Italy
关键词
antibody structure; loop conformation; canonical structures; antigen-binding; ligand-induced conformational change;
D O I
10.1006/jmbi.1997.1442
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
Antigen-combining sites of antibodies are constructed from six loops from VL and VH domains. The third hypervariable region of the heavy chain is far more variable than the others in length, sequence and structure, and was not included in the canonical-structure description of the conformational repertoire of the three hypervariable regions of V-K chains and the first two of VH chains. Here we present an analysis of the conformations of the third hypervariable region of VH domains (the H3 regions) in antibodies of known structure. We define the H3 region as comprising the residues between 92Cys and 104Gly. We divide it into a torso comprising residues proximal to the framework, four residues from the N terminus and six residues from the C terminus, and a head. There are two major classes of H3 structures that have more than ten residues between 92Cys and 104Gly: (1) the conformation of the torso has a beta-bulge at residue 101, and (2) the torso does not contain a bulge, but continues the regular hydrogen-bonding pattern of the beta-sheet hairpin. The choice of bulged versus non-bulged torso conformation is dictated primarily by the sequence, through the formation of a salt bridge between the side-chains of an Arg or Lys at position 94 and an Asp at position 101. Thus the torso region appears to have a Limited repertoire of conformations, as in the canonical structure model of other antigen-binding loops. The heads or apices of the loops have a very wide variety of conformations. In shorter H3 regions, and in those containing the non-bulged torso conformation, the heads follow the rules relating sequence to structure in short hairpins. We surveyed the heads of longer H3 regions, finding that those with bulged torsos present many very different conformations of the head. We recognize that H3, unlike the other five antigen-binding loops, has a conformation that depends strongly on the environment, and we have analysed the interactions of H3 with residues elsewhere in the VH domain, in the VL domain, and with Ligands, and their effects on the conformation of H3. We tested these results by attempts to predict the conformations of H3 regions in antibody structures solved after the results were derived. The general conclusion of this work is that the conformation of H3 shows some regularities, from which rules relating sequence to conformation can be stated, but to a less complete degree than for the other five antigen-binding loops. Accurate prediction of the torso conformation is possible in most cases; predictions of the conformation of the head is possible in some cases. However, our understanding of the sequence-structure relationships has reduced the uncertainty to no more than a few residues at the apex of the H3 region. (C) 1998 Academic Press Limited.
引用
收藏
页码:269 / 294
页数:26
相关论文
共 82 条
[1]   Standard conformations for the canonical structures of immunoglobulins [J].
AlLazikani, B ;
Lesk, AM ;
Chothia, C .
JOURNAL OF MOLECULAR BIOLOGY, 1997, 273 (04) :927-948
[2]   A CONFORMATION OF CYCLOSPORINE-A IN AQUEOUS ENVIRONMENT REVEALED BY THE X-RAY STRUCTURE OF A CYCLOSPORINE-FAB COMPLEX [J].
ALTSCHUH, D ;
VIX, O ;
REES, B ;
THIERRY, JC .
SCIENCE, 1992, 256 (5053) :92-94
[3]   3-DIMENSIONAL STRUCTURE DETERMINATION OF AN ANTI-2-PHENYLOXAZOLONE ANTIBODY - THE ROLE OF SOMATIC MUTATION AND HEAVY LIGHT CHAIN PAIRING IN THE MATURATION OF AN IMMUNE-RESPONSE [J].
ALZARI, PM ;
SPINELLI, S ;
MARIUZZA, RA ;
BOULOT, G ;
POLJAK, RJ ;
JARVIS, JM ;
MILSTEIN, C .
EMBO JOURNAL, 1990, 9 (12) :3807-3814
[4]   3-DIMENSIONAL STRUCTURE OF AN ANTI-STEROID FAB' AND PROGESTERONE FAB' COMPLEX [J].
AREVALO, JH ;
STURA, EA ;
TAUSSIG, MJ ;
WILSON, IA .
JOURNAL OF MOLECULAR BIOLOGY, 1993, 231 (01) :103-118
[5]   PROTEIN DATA BANK - COMPUTER-BASED ARCHIVAL FILE FOR MACROMOLECULAR STRUCTURES [J].
BERNSTEIN, FC ;
KOETZLE, TF ;
WILLIAMS, GJB ;
MEYER, EF ;
BRICE, MD ;
RODGERS, JR ;
KENNARD, O ;
SHIMANOUCHI, T ;
TASUMI, M .
JOURNAL OF MOLECULAR BIOLOGY, 1977, 112 (03) :535-542
[6]   BOUND WATER-MOLECULES AND CONFORMATIONAL STABILIZATION HELP MEDIATE AN ANTIGEN-ANTIBODY ASSOCIATION [J].
BHAT, TN ;
BENTLEY, GA ;
BOULOT, G ;
GREENE, MI ;
TELLO, D ;
DALLACQUA, W ;
SOUCHON, H ;
SCHWARZ, FP ;
MARIUZZA, RA ;
POLJAK, RJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (03) :1089-1093
[7]   REFINED 3-DIMENSIONAL STRUCTURE OF THE FAB FRAGMENT OF A MURINE IGG1,LAMBDA ANTIBODY [J].
BIZEBARD, T ;
DANIELS, R ;
KAHN, R ;
GOLINELLIPIMPANEAU, B ;
SKEHEL, JJ ;
KNOSSOW, M .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :768-777
[8]   3-DIMENSIONAL STRUCTURES OF THE FREE AND THE ANTIGEN-COMPLEXED FAB FROM MONOCLONAL ANTILYSOZYME ANTIBODY-D44.1 [J].
BRADEN, BC ;
SOUCHON, H ;
EISELE, JL ;
BENTLEY, GA ;
BHAT, TN ;
NAVAZA, J ;
POLJAK, RJ .
JOURNAL OF MOLECULAR BIOLOGY, 1994, 243 (04) :767-781
[9]   STRUCTURE OF ANTIBODY HYPERVARIABLE LOOPS REPRODUCED BY A CONFORMATIONAL SEARCH ALGORITHM [J].
BRUCCOLERI, RE ;
HABER, E ;
NOVOTNY, J .
NATURE, 1988, 335 (6190) :564-568
[10]   2.9 A-RESOLUTION STRUCTURE OF AN ANTI-DINITROPHENYL-SPIN-LABEL MONOCLONAL-ANTIBODY FAB FRAGMENT WITH BOUND HAPTEN [J].
BRUNGER, AT ;
LEAHY, DJ ;
HYNES, TR ;
FOX, RO .
JOURNAL OF MOLECULAR BIOLOGY, 1991, 221 (01) :239-256