3S4S
Crystal structure of CD4 mutant bound to HLA-DR1
Summary for 3S4S
| Entry DOI | 10.2210/pdb3s4s/pdb |
| Related | 3S5L |
| Descriptor | HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-1 beta chain, Hemagglutinin peptide, ... (6 entities in total) |
| Functional Keywords | protein-protein complex, immune system |
| Biological source | Homo sapiens (human) More |
| Cellular location | Cell membrane; Single-pass type I membrane protein: P01903 P04229 P01730 |
| Total number of polymer chains | 8 |
| Total formula weight | 133014.05 |
| Authors | |
| Primary citation | Wang, X.X.,Li, Y.,Yin, Y.,Mo, M.,Wang, Q.,Gao, W.,Wang, L.,Mariuzza, R.A. Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4-HLA-DR1 complex. Proc.Natl.Acad.Sci.USA, 108:15960-15965, 2011 Cited by PubMed Abstract: Helper T-cell activation generally requires the coreceptor CD4, which binds MHC class II molecules. A remarkable feature of the CD4-MHC class II interaction is its exceptionally low affinity, which ranges from K(D) = ∼200 μM to >2 mM. Investigating the biological role of the much lower affinity of this interaction than those of other cell-cell recognition molecules will require CD4 mutants with enhanced binding to MHC class II for testing in models of T-cell development. To this end, we used in vitro-directed evolution to increase the affinity of human CD4 for HLA-DR1. A mutant CD4 library was displayed on the surface of yeast and selected using HLA-DR1 tetramers or monomers, resulting in isolation of a CD4 clone containing 11 mutations. Reversion mutagenesis showed that most of the affinity increase derived from just two substitutions, Gln40Tyr and Thr45Trp. A CD4 variant bearing these mutations bound HLA-DR1 with K(D) = 8.8 μM, compared with >400 μM for wild-type CD4. To understand the basis for improved affinity, we determined the structure of this CD4 variant in complex with HLA-DR1 to 2.4 Å resolution. The structure provides an atomic-level description of the CD4-binding site on MHC class II and reveals how CD4 recognizes highly polymorphic HLA-DR, -DP, and -DQ molecules by targeting invariant residues in their α2 and β2 domains. In addition, the CD4 mutants reported here constitute unique tools for probing the influence of CD4 affinity on T-cell activation and development. PubMed: 21900604DOI: 10.1073/pnas.1109438108 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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