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Human CD8 is a T cell coreceptor, which binds to pHLA I and plays a pivotal role in the activation of cytotoxic T lymphocytes. Soluble recombinant CD8 alphaalpha has been shown to antagonize T cell activation, both in vitro and in vivo. However, because of a very low affinity for pHLA I, high concentrations of soluble CD8 alphaalpha are required for efficient inhibition. Based upon our knowledge of the wild-type CD8/pHLA I structure, we have designed and produced a mutated form of soluble CD8 alphaalpha that binds to pHLA I with approximately fourfold higher affinity. We have characterized the binding of the high affinity CD8 mutant using surface plasmon resonance and determined its structure at 2.1 A resolution using X-ray crystallography. The analysis of this structure suggests that the higher affinity is achieved by providing a larger side chain that allows for an optimal contact to be made between the HLA alpha3 loop and the mutated CDR-like loops of CD8.

Original publication

DOI

10.1002/prot.21176

Type

Journal article

Journal

Proteins

Publication Date

01/04/2007

Volume

67

Pages

65 - 74

Keywords

Amino Acid Substitution, CD8 Antigens, Computational Biology, Computer Simulation, Crystallization, Crystallography, X-Ray, Models, Molecular, Protein Engineering, Protein Folding, Surface Plasmon Resonance