Crystal structure of the human T cell receptor CD3εγ heterodimer complexed to the therapeutic mAb OKT3

doi:10.1073/pnas.0402295101

Crystal structure of the human T cell receptor CD3εγ heterodimer complexed to the therapeutic mAb OKT3

^*Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia; and ^‡The Protein Crystallography Unit, Monash Centre for Synchrotron Science, and Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia

Communicated by Peter Doherty, University of Melbourne, Parkville, Australia, March 31, 2004 (received for review March 3, 2004)

Abstract

The CD3εγ heterodimer is essential for expression and function of the T cell receptor. The crystal structure of the human CD3εγ heterodimer is described to 2.1-Å resolution complexed with OKT3, a therapeutic mAb that not only activates and tolerizes mature T cells but also induces regulatory T cells. The mode of CD3εγ dimerization provides a general structural basis for CD3 assembly and maps candidate T cell antigen receptor docking sites, including a duplicated linear region rich in acidic residues that is unique to human CD3ε. OKT3 binds to an atypically small area of CD3ε and has a low affinity for the isolated CD3εγ heterodimer. The structure of the OKT3/CD3εγ complex has implications for T cell signaling and therapeutic design.

Footnotes

↵ § To whom correspondence may be addressed. E-mail: jamie.rossjohn{at}med.monash.edu.au or jamesm1{at}unimelb.edu.au.
↵ † L.K.-N. and M.A.D. contributed equally to this work.
Abbreviations: TcR, T cell receptor; pMHC, peptide-MHC; SC, shape complementarity; BSA, buried surface area.
Data deposition: The crystal structure has been deposited in the Protein Data Bank, www.pdb.org (PBD ID code 1SY6).