Literature DB >> 12121653

Noncompetitive antibody neutralization of IL-10 revealed by protein engineering and x-ray crystallography.

Kristopher Josephson1, Brandi C Jones, Leigh J Walter, Ruth DiGiacomo, Stephen R Indelicato, Mark R Walter.   

Abstract

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 A 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.

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Year:  2002        PMID： 12121653     DOI： 10.1016/s0969-2126(02)00791-8

Source DB:  PubMed          Journal:  Structure        ISSN： 0969-2126            Impact factor:   5.006


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