Noncompetitive Antibody Neutralization of IL-10 Revealed by Protein Engineering and X-Ray Crystallography

IL-10 is a dimeric cytokine that must engage its high-affinity cell surface receptor, IL-10R1, to induce multiple cellular activities. Here we report the 1.9 Å crystal structure of an engineered IL-10 monomer (IL-10M1) in complex with a neutralizing Fab fragment (9D7Fab). 9D7Fab and IL-10R1 bind dis...

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Bibliographic Details
Published in:Structure (London) 2002-07, Vol.10 (7), p.981-987
Main Authors: Josephson, Kristopher, Jones, Brandi C, Walter, Leigh J, DiGiacomo, Ruth, Indelicato, Stephen R, Walter, Mark R
Format: Article
Language:English
Subjects:
Allosteric Regulation
crystal structure
Crystallography, X-Ray
cytokine
Herpesvirus 4, Human - chemistry
IL-10
Immunoglobulin Fab Fragments - chemistry
Interleukin-10 - chemistry
Interleukin-10 - genetics
Models, Molecular
Mutation
neutralizing antibody
noncompetitive
Protein Conformation
Protein Engineering
Receptors, Interleukin - chemistry
Receptors, Interleukin-10
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Summary:IL-10 is a dimeric cytokine that must engage its high-affinity cell surface receptor, IL-10R1, to induce multiple cellular activities. Here we report the 1.9 Å crystal structure of an engineered IL-10 monomer (IL-10M1) in complex with a neutralizing Fab fragment (9D7Fab). 9D7Fab and IL-10R1 bind distinct nonoverlapping surfaces on IL-10M1. Antagonism of the IL-10M1/IL-10R1 interaction is the result of 9D7Fab-induced conformational changes in the CD loop of IL-10M1 that indirectly alter the structure of the IL-10R1 binding site. A single mutation (Ile87Ala) in the same CD loop region of the Epstein-Barr virus IL-10 (ebvIL-10) also reduces IL-10R1 binding affinity, suggesting that ebvIL-10 and 9D7Fab use similar allosteric mechanisms to modulate IL-10R1 affinity and biological activity.
ISSN:0969-2126
1878-4186
DOI:10.1016/S0969-2126(02)00791-8