Antibody multispecificity mediated by conformational diversity

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Antibodies are crucial for adaptive immunity, recognizing specific antigens.
• The traditional view holds that antibodies possess a single, fixed binding site conformation.

Purpose of the Study:

• To investigate the conformational flexibility of a single antibody.
• To understand how conformational changes influence antigen binding and antibody function.

Main Methods:

• X-ray crystallography to determine antibody structures.
• Pre-steady-state kinetics to analyze binding dynamics.
• Repertoire selection to identify specific antibody-antigen interactions.

Main Results:

• A single antibody demonstrated distinct binding-site conformations, enabling binding to unrelated antigens.
• An equilibrium between antibody isomers was identified, with one isomer showing promiscuous low-affinity binding.
• Induced-fit isomerization resulted in high-affinity binding with a deep, narrow site.
• A protein antigen utilized a different antibody isomer with a wide, shallow binding site.

Conclusions:

• Antibody conformational diversity allows a single antibody sequence to perform multiple functions.
• This flexibility enhances the effective size of the antibody repertoire.
• However, conformational diversity may also predispose individuals to autoimmunity and allergies.