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Acta Crystallogr D Biol Crystallogr. 2008 Jun;64(Pt 6):700-4. doi: 10.1107/S0907444908007877. Epub 2008 May 14.

Structural characterization of a human Fc fragment engineered for lack of effector functions.

Author information

1
Department of Antibody Discovery and Protein Engineering, MedImmune Inc., One MedImmune Way, Gaithersburg, MD 20878, USA.

Abstract

The first three-dimensional structure of a human Fc fragment genetically engineered for the elimination of its ability to mediate antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity is reported. When introduced into the lower hinge and CH2 domain of human IgG1 molecules, the triple mutation L234F/L235E/P331S ('TM') causes a profound decrease in their binding to human CD64, CD32A, CD16 and C1q. Enzymatically produced Fc/TM fragment was crystallized and its structure was solved at a resolution of 2.3 A using molecular replacement. This study revealed that the three-dimensional structure of Fc/TM is very similar to those of other human Fc fragments in the experimentally visible region spanning residues 236-445. Thus, the dramatic broad-ranging effects of TM on IgG binding to several effector molecules cannot be explained in terms of major structural rearrangements in this portion of the Fc.

PMID:
18560159
PMCID:
PMC2467532
DOI:
10.1107/S0907444908007877
[Indexed for MEDLINE]
Free PMC Article

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