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High-resolution crystal structure of the Fab-fragments of a family of mouse catalytic antibodies with esterase activity.

Ruzheinikov SN, Muranova TA, Sedelnikova SE, Partridge LJ, Blackburn GM, Murray IA, Kakinuma H, Takahashi-Ando N, Shimazaki K, Sun J, Nishi Y, Rice DW
J Mol Biol 332 423-35 (2003)
Related entries: 1mh5, 1mie, 1mj7, 1mj8, 1mju

Cited: 12 times
EuropePMC logo PMID: 12948492

Abstract

The crystal structures of four related Fab fragments of a family of catalytic antibodies displaying differential levels of esterase activity have been solved in the presence and in the absence of the transition-state analogue (TSA) that was used to elicit the immune response. The electron density maps show that the TSA conformation is essentially identical, with limited changes on hapten binding. Interactions with the TSA explain the specificity for the D rather than the L-isomer of the substrate. Differences in the residues in the hapten-binding pocket, which increase hydrophobicity, appear to correlate with an increase in the affinity of the antibodies for their substrate. Analysis of the structures at the active site reveals a network of conserved hydrogen bond contacts between the TSA and the antibodies, and points to a critical role of two conserved residues, HisL91 and LysH95, in catalysis. However, these two key residues are set into very different contexts in their respective structures, with an apparent direct correlation between the catalytic power of the antibodies and the complexity of their interactions with the rest of the protein. This suggests that the catalytic efficiency may be controlled by contacts arising from a second sphere of residues at the periphery of the active site.

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  1. Antibody structure, instability, and formulation. Wang W, Singh S, Zeng DL, King K, Nema S. J Pharm Sci 96 1-26 (2007)

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  1. A new clustering of antibody CDR loop conformations. North B, Lehmann A, Dunbrack RL. J. Mol. Biol. 406 228-256 (2011)
  2. Epitope mapping and structural basis for the recognition of phosphorylated tau by the anti-tau antibody AT8. Malia TJ, Teplyakov A, Ernst R, Wu SJ, Lacy ER, Liu X, Vandermeeren M, Mercken M, Luo J, Sweet RW, Gilliland GL. Proteins 84 427-434 (2016)
  3. Stabilization and humanization of a single-chain Fv antibody fragment specific for human lymphocyte antigen CD19 by designed point mutations and CDR-grafting onto a human framework. Kügler M, Stein C, Schwenkert M, Saul D, Vockentanz L, Huber T, Wetzel SK, Scholz O, Plückthun A, Honegger A, Fey GH. Protein Eng. Des. Sel. 22 135-147 (2009)
  4. Complete reaction cycle of a cocaine catalytic antibody at atomic resolution. Zhu X, Dickerson TJ, Rogers CJ, Kaufmann GF, Mee JM, McKenzie KM, Janda KD, Wilson IA. Structure 14 205-216 (2006)
  5. Mutational and inhibitory analysis of a catalytic antibody. Implication for drug discovery. Phichith D, Bun S, Padiolleau-Lefèvre S, Banh S, Thomas D, Friboulet A, Avalle B. Mol. Immunol. 47 348-356 (2009)
  6. Structure of the Fab fragment of the anti-murine EGFR antibody 7A7 and exploration of its receptor binding site. Talavera A, Mackenzie J, Garrido G, Friemann R, López-Requena A, Moreno E, Krengel U. Mol. Immunol. 48 1578-1585 (2011)
  7. Comparison of joining and constant κ-light chain regions in different cattle breeds. Stein SK, Diesterbeck US, Aboelhassan DM, Czerny CP. Anim. Genet. 43 776-780 (2012)
  8. Molecular mechanisms of improvement of hydrolytic antibody 6D9 by site-directed mutagenesis. Takahashi-Ando N, Shimazaki K, Kakinuma H, Fujii I, Nishi Y. J. Biochem. 140 509-515 (2006)


Related citations provided by authors (1)

  1. The preparation and crystallization of Fab fragments of a family of mouse esterolytic catalytic antibodies and their complexes with a transition-state analogue.. Muranova TA, Ruzheinikov SN, Sedelnikova SE, Moir A, Partridge LJ, Kakinuma H, Takahashi N, Shimazaki K, Sun J, Nishi Y, Rice DW Acta Crystallogr D Biol Crystallogr 57 1192-5 (2001)

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