Computational design and crystal structure of an enhanced affinity mutant human CD8 αα coreceptor

Cole, David ORCID: https://orcid.org/0000-0003-0028-9396, Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369, Boulter, Jonathan M., Sami, Malkit, Vuidepot, Anne-lise, Glick, Meir, Gao, Feng, Bell, John I., Jakobsen, Bent K. and Gao, George F. 2007. Computational design and crystal structure of an enhanced affinity mutant human CD8 αα coreceptor. Proteins: Structure, Function and Bioinformatics 67 (1) , pp. 65-74. 10.1002/prot.21176

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Abstract

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 αα 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 αα 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 αα 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 Å 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 α3 loop and the mutated CDR-like loops of CD8.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	CD8; coreceptor; soluble protein; crystal structure; KD; protein engineering; immunotherapy; immune-suppressor.
Publisher:	Wiley-Blackwell
ISSN:	0887-3585
Last Modified:	25 Oct 2022 09:54
URI:	https://orca.cardiff.ac.uk/id/eprint/60460

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