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Three-Dimensional Structures of Immunoglobulins: Nomenclature and Structural Diversity

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This document explores the intricate three-dimensional structures of immunoglobulins, detailing the antibody domain and fragment nomenclature. It discusses the structural basis of diversity in immunoglobulins, including the immunoglobulin fold, binding site categories, and the biochemical mechanisms of antigen recognition. Key concepts such as conformational changes upon binding, antibody flexibility, and the relationship between variable and constant regions are highlighted. The content elaborates on the assembly of CDRs and the canonical structures that define the antigen-antibody interactions.

#three-dimensional structures of immunoglobulins: nomenclature and structural diversity #three-dimensional structures of immunoglobulins: nomenclature and structural diversity ppt #powerpoint #presentation
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Three-Dimensional Structures of Immunoglobulins: Nomenclature and Structural Diversity
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  1. David Rose drose@oci.utoronto.ca Three-Dimensional Structures of Immunoglobulins - Antibody Domain and Fragment Nomenclature - Structural basis of Diversity - Immunoglobulin Fold - Shapes / Categories of Binding Sites - Biochemical Basis of Binding / Recognition - Conformational Changes on Binding - Antibody Flexibility - Other Immunoglobulin- like Molecules

  2. R.R. Porter, Nobel Lecture, 1972

  3. (Fab’)2 Fv fragment

  4. Antibody Domain and Fragment Nomenclature - Variable, Constant Regions Defined by similarity of amino-acid sequence between antibodies Each forms a structural unit (Ig fold) - Heavy Chains 1 variable domain (N-terminus): Vh 3 (IgG) or more constant domains: Ch1 - Ch3 constant domains define antibody class - Light Chains 1 variable domain (N-terminus): Vl 1 constant domain: Cl - Antigen Binding Fragment (Fab) Vl/Vh - Cl/Ch1 heterodimer - Constant (crystallizable) Fragment (Fc) Ch2-Ch3 homodimer - Variable Fragment (Fv) Vl/Vh heterodimer - Epitope: Part of the antigen recognized by the antibody - Paratope: Antibody recognition region

  5. - Variability Plots v = num different residue types / Freq (most common) - Relationship to V(D)J gene segments

  6. Kappa light chain V regions

  7. IgG heavy chain V regions

  8. V V V V CL J J J J J CL V V J CL Light Chain V D J C Heavy Chain

  9. Immunoglobulin Fold: Each region (V,C) forms a -sheet sandwich 110-120 residues Light Chain Variable Region

  10. Light Chain Constant Region

  11. - Framework / Complementarity -Determining Regions (CDRs) (Hypervariable regions) assemble to make up the antibody binding region. - Fab/Fv binding site (combining site) 6 CDRs: 3 Light Chain + 3 Heavy Chain L1-3, H1-3 - Canonical CDR structures Chothia and Lesk L1-3, H1, H2 well defined by loop structures

  12. Canonical forms of CDR loops. Al-lazikani, Lesk & Chothia, J Mol Biol (1997) 273:927

  13. Canonical forms,  chain L1 CDRs

  14. H3 CDR’s: 12-residue length Al-lazikani, Lesk & Chothia J Mol Biol (2000) 295:979

  15. Shapes / Categories of Binding sites • - Flat: • mostly surface residues from both antibody and antigen. Frequently • discontinuous regions of antigen • - Groove / Crevice: • Binds to stretches of antigen, usually continuous • - Pocket: • Usually small molecule antigens, tight loops, or ends of polymers that • penetrate a small pocket.

  16. Combining Site Shapes Pocket Groove Flat

  17. Types of Antigens: 1. Small Molecules (haptens) Pocket-shaped shape complementarity electrostatics / hydrogen bonds (enthalpy-driven) High association constants (108 - 109 M-1)

  18. 2. Proteins a. discontinuous flat shaped hydrophobic (elimination of water) Van der Waals hydrogen bonds some entropic contribution Buried surface ~700-800 Å2 Moderate - high association constants (106 - 108 M-1)

  19. b. continuous groove / crevice extended loop on antigen (usually -turn but can be -helix) higher entropic cost Hydrophobic, entropic, van der Waals shape complementarity Induced fit of antibody and/or antigen

  20. Fab F11.2.32 HIV-1 protease peptide complex Lescar et al, J Mol Biol (1997) 267: 1207

  21. Fab 17/9 complex with peptide from Influenza virus hemagglutinin Rini, Schulze-Gahmen & Wilson (1992) Science 255:959

  22. MRK-16 Fab structure: Vasudevan, Tsuruo and Rose, J. Biol Chem (1998) 273:25413

  23. Jean M. H. van den Elsen, Douglas A. Kuntz, Flip J. Hoedemaeker, and David R. Rose Antibody C219 recognizes an -helical epitope on P-glycoprotein PNAS 96: 13679-13684

  24. 3. Carbohydrate / polysaccharide Groove - shaped (chain binder) or pocket-shaped (end binder) Hydrophobic (especially aromatic) some hydrogen bonds water can be used as coordinating ligand High entropic cost Lower buried surface (500-600 Å2) Lower association constants (104 - 105 M-1)

  25. Fab Se155.4 complex with Salmonella cell-surface antigen Cygler, Rose & Bundle (1991) Science 253:442

  26. Binding of cholera O1 antigen to Fab S-20-4 Villeneuve et al, PNAS (2000) 97:8433

  27. Conformational changes / flexibility Induced fit antibody binding site plasticity epitope Antibody flexibility domain:domain interaction changes antigen binding tether links in intact IgG structure

  28. Antibody conformational change on complexation: Fab 17-IA with HRV-14 Smith et al (1996) Nature 383:350

  29. Epitope Conformational change on complexation : HIV Protease

  30. Epitope conformational changeon complexation: Flu hemagglutinin

  31. Conformational Change on Antigen Binding

  32. Crystal Structure of an Intact IgG Harris LJ, Skaletsky E, McPherson A. (1998) J Mol Biol 275:861