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Title: Structure Activity Relationships of Monocyte Chemoattractant Proteins in Complex with a Blocking Antibody

Abstract

Monocyte chemoattractant proteins (MCPs) are cytokines that direct immune cells bearing appropriate receptors to sites of inflammation or injury and are therefore attractive therapeutic targets for inhibitory molecules. 11K2 is a blocking mouse monoclonal antibody active against several human and murine MCPs. A 2.5 Angstroms structure of the Fab fragment of this antibody in complex with human MCP-1 has been solved. The Fab blocks CCR2 receptor binding to MCP-1 through an adjacent but distinct binding site. The orientation of the Fab indicates that a single MCP-1 dimer will bind two 11K2 antibodies. Several key residues on the antibody and on human MCPs were predicted to be involved in antibody selectivity. Mutational analysis of these residues confirms their involvement in the antibody- chemokine interaction. In addition to mutations that decreased or disrupted binding, one antibody mutation resulted in a 70-fold increase in affinity for human MCP-2. A key residue missing in human MCP-3, a chemokine not recognized by the antibody, was identified and engineering the preferred residue into the chemokine conferred binding to the antibody.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
914024
Report Number(s):
BNL-78592-2007-JA
TRN: US200804%%438
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Protein Eng.; Journal Volume: 19
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AFFINITY; ANTIBODIES; BEARINGS; DIMERS; INFLAMMATION; LYMPHOKINES; MONOCYTES; MUTATIONS; ORIENTATION; PROTEINS; RESIDUES; STRUCTURE-ACTIVITY RELATIONSHIPS; TARGETS; national synchrotron light source

Citation Formats

Reid,C., Rushe, M., Jarpe, M., Van Vlijmen, H., Dolinski, B., Qian, F., Cachero, T., Cuervo, H., Yanachkova, M., and et al.. Structure Activity Relationships of Monocyte Chemoattractant Proteins in Complex with a Blocking Antibody. United States: N. p., 2006. Web. doi:10.1093/protein/gzl015.
Reid,C., Rushe, M., Jarpe, M., Van Vlijmen, H., Dolinski, B., Qian, F., Cachero, T., Cuervo, H., Yanachkova, M., & et al.. Structure Activity Relationships of Monocyte Chemoattractant Proteins in Complex with a Blocking Antibody. United States. doi:10.1093/protein/gzl015.
Reid,C., Rushe, M., Jarpe, M., Van Vlijmen, H., Dolinski, B., Qian, F., Cachero, T., Cuervo, H., Yanachkova, M., and et al.. Sun . "Structure Activity Relationships of Monocyte Chemoattractant Proteins in Complex with a Blocking Antibody". United States. doi:10.1093/protein/gzl015.
@article{osti_914024,
title = {Structure Activity Relationships of Monocyte Chemoattractant Proteins in Complex with a Blocking Antibody},
author = {Reid,C. and Rushe, M. and Jarpe, M. and Van Vlijmen, H. and Dolinski, B. and Qian, F. and Cachero, T. and Cuervo, H. and Yanachkova, M. and et al.},
abstractNote = {Monocyte chemoattractant proteins (MCPs) are cytokines that direct immune cells bearing appropriate receptors to sites of inflammation or injury and are therefore attractive therapeutic targets for inhibitory molecules. 11K2 is a blocking mouse monoclonal antibody active against several human and murine MCPs. A 2.5 Angstroms structure of the Fab fragment of this antibody in complex with human MCP-1 has been solved. The Fab blocks CCR2 receptor binding to MCP-1 through an adjacent but distinct binding site. The orientation of the Fab indicates that a single MCP-1 dimer will bind two 11K2 antibodies. Several key residues on the antibody and on human MCPs were predicted to be involved in antibody selectivity. Mutational analysis of these residues confirms their involvement in the antibody- chemokine interaction. In addition to mutations that decreased or disrupted binding, one antibody mutation resulted in a 70-fold increase in affinity for human MCP-2. A key residue missing in human MCP-3, a chemokine not recognized by the antibody, was identified and engineering the preferred residue into the chemokine conferred binding to the antibody.},
doi = {10.1093/protein/gzl015},
journal = {Protein Eng.},
number = ,
volume = 19,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}