About: PURPOSE: To analyze contribution of short aggregation-prone regions (APRs), which may self-associate via cross-β motif and were earlier identified in therapeutic mAbs, towards antigen recognition via structural analyses of antibody-antigen complexes. METHODS: A dataset of 29 publically available high-resolution crystal structures of Fab-antigen complexes was collected. Contribution of APRs towards the surface areas of the Fabs buried by the cognate antigens was computed. Propensities of amino acids to occur in APRs and to be involved in antigen binding were compared. Coincidence between APRs and individual CDR loops was examined. RESULTS: All Fabs in the dataset contain at least one APR in CDR loops and adjacent framework β-strands. The average contribution of APRs towards buried surface area of Fabs is 16.0 ± 10.7%. Aggregation and antigen recognition may be coupled via aromatic residues (Tyr, Trp), which occur with high propensities in both APRs and antigen binding sites. APRs are infrequent in the heavy chain CDR 3 (H3) loops (7%), but are frequent in H2 loops (45%). CONCLUSIONS: Co-incidence of APRs with antigen recognition sites can potentially lead to the loss of function upon aggregation. Rational structure-based design or selection strategies are suggested for biotherapeutics with improved druggability while maintaining potency. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11095-010-0143-5) contains supplementary material, which is available to authorized users.   Goto Sponge  NotDistinct  Permalink

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  • PURPOSE: To analyze contribution of short aggregation-prone regions (APRs), which may self-associate via cross-β motif and were earlier identified in therapeutic mAbs, towards antigen recognition via structural analyses of antibody-antigen complexes. METHODS: A dataset of 29 publically available high-resolution crystal structures of Fab-antigen complexes was collected. Contribution of APRs towards the surface areas of the Fabs buried by the cognate antigens was computed. Propensities of amino acids to occur in APRs and to be involved in antigen binding were compared. Coincidence between APRs and individual CDR loops was examined. RESULTS: All Fabs in the dataset contain at least one APR in CDR loops and adjacent framework β-strands. The average contribution of APRs towards buried surface area of Fabs is 16.0 ± 10.7%. Aggregation and antigen recognition may be coupled via aromatic residues (Tyr, Trp), which occur with high propensities in both APRs and antigen binding sites. APRs are infrequent in the heavy chain CDR 3 (H3) loops (7%), but are frequent in H2 loops (45%). CONCLUSIONS: Co-incidence of APRs with antigen recognition sites can potentially lead to the loss of function upon aggregation. Rational structure-based design or selection strategies are suggested for biotherapeutics with improved druggability while maintaining potency. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11095-010-0143-5) contains supplementary material, which is available to authorized users.
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  • Immunology
  • Immune system
  • NCAA Division I
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