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Three-dimensional structure of the murine anti-p-azophenylarsonate Fab 36-71. 2. Structural basis of hapten binding and idiotypy

Strong, Roland K. and Petsko, Gregory A. and Sharon, Jacqueline and Margolies, Michael N. (1991) Three-dimensional structure of the murine anti-p-azophenylarsonate Fab 36-71. 2. Structural basis of hapten binding and idiotypy. Biochemistry, 30 (15). pp. 3749-3757. ISSN 0006-2960. doi:10.1021/bi00229a023.

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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 R19.9 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 R19.9 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 R19.9 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 R19.9, and does not interact with any of these 16 sites. Comparing the structures of 36-71 and R19.9 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. The substitutions in the light chain appear to affect the binding constant for hapten by altering the overall conformation of the third heavy-chain complementarity-determining region. Regions where the solventaccessible surfaces of 36-71 and R19.9 differ have been located. Presumably, these differences in accessible surface area account for the lack of reactivity with anti-idiotypic antibodies for R19.9 versus 36-71. Positions in the sequence where differences are known to affect the binding of anti-p-azophenylarsonate antibodies to monoclonal anti-idiotope antibodies generally map to the region around the hapten-binding site. Not unexpectedly, substitutions at these locations in the sequence do not always appear to affect anti-idiotope binding directly but may alter idiotype/anti-idiotype affinity indirectly by altering the conformation of contact residues.

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Additional Information:© 1991 American Chemical Society. Published in print 16 April 1991. This work was supported by the US. Public Health Service through NIH Grants CA 24432, HL19259, and AI 23909. J.S. is a recipient of an ACS scholar award. We thank Dr. Tom Smith (Purdue) for supplying his programs MacFrodo and MacPrep with which many of the figures were prepared and Dr. Robert Campbell (National Research Council Canada) for his advice.
Funding AgencyGrant Number
NIHCA 24432
NIHHL 19259
NIHAI 23909
American Cancer SocietyUNSPECIFIED
Issue or Number:15
Record Number:CaltechAUTHORS:20180212-095413054
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Official Citation:Three-dimensional structure of the murine anti-p-azophenylarsonate Fab 36-71. 2. Structural basis of hapten binding and idiotypy Roland K. Strong, Gregory A. Petsko, Jacqueline Sharon, and Michael N. Margolies Biochemistry 1991 30 (15), 3749-3757 DOI: 10.1021/bi00229a023
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84786
Deposited By: Ruth Sustaita
Deposited On:13 Feb 2018 21:35
Last Modified:15 Nov 2021 20:22

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