Three-dimensional structure of murine anti-p-azophenylarsonate Fab 36-71. 2. Structural basis of hapten binding and idiotypy.
Comparison between the structures and solvent-accessible surfaces of the antigen-binding fragments of two murine anti-p-azophenylarsonate monoclonal antibodies, one bearing a major cross-reactive idiotype of A/J strain mice (36-71) and one lacking the idiotype (R19.9; Lascombe et al., 1989), highlight the structural basis for the determination of hapten affinity and idiotypy. Since the sequence of R 19.9 is identical with the germline-encoded sequence at 16 positions in both heavy-chain and light-chain variable regions where somatic mutations and junctional differences have occurred to produce the 36-71 sequence, the structure of R 19.9 can be used to model the structure of the germline-encoded antibody (36-65) in the regions around these sites. These 16 sequence differences exclude the third heavy-chain complementarity-determining region because R 19.9 utilizes a D gene segment not associated with the predominant idiotype, which is 4 residues longer than the canonical D gene segment utilized in the sequences of 36-71 and 36-65. This difference between the structures of R 19.9 and 36-71 does not affect the validity of using the structure of R 19.9 to model the structure of 36-65 since the third heavy-chain complementarity-determining region is highly solvent-exposed in both 36-71 and R 19.9, and does not interact with any of these 16 sites. Comparing the structures of 36-71 and R 19.9 suggests that only three of the differences in the heavy-chain sequences, and three of the differences in the light-chain sequences of 36-71 and 36-65, increase the affinity for hapten.(ABSTRACT TRUNCATED AT 250 WORDS)
Strong
R K
RK
California Institute of Technology, Pasadena 91125.
Petsko
G A
GA
Sharon
J
J
Margolies
M N
MN
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D006241:Haptens / Q000276:immunology*; D007127:Immunoglobulin Constant Regions; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000276:immunology; D007130:Immunoglobulin Idiotypes; D007135:Immunoglobulin Variable Region; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013237:Stereoisomerism; D013696:Temperature; D010132:p-Azobenzenearsonate / Q000737:chemistry* / Q000276:immunology
D000911:Antibodies, Monoclonal; D006241:Haptens; D007127:Immunoglobulin Constant Regions; D007140:Immunoglobulin Fab Fragments; D007130:Immunoglobulin Idiotypes; D007135:Immunoglobulin Variable Region; D010132:p-Azobenzenearsonate