9C6X

Crystal Structure of a single chain trimer composed of HLA-B*39:01 Y84C variant, beta-2microglobulin, and NRVMLPKAA peptide from NLRP2

Summary for 9C6X

• Entry DOI: 10.2210/pdb9c6x/pdb
• Related: 4O2E 9C6V 9C6W
• Descriptor: NACHT, LRR and PYD domains-containing protein 2,Beta-2-microglobulin,MHC class I antigen, 1-ETHOXY-2-(2-ETHOXYETHOXY)ETHANE, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: hla class i histocompatibility antigen, b-39 alpha chain, beta-2-microglobulin, nlrp2, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 46990.76

Authors

Sharma, R.,Amdare, N.P.,Celikgil, A.,Garforth, S.J.,DiLorenzo, T.P.,Almo, S.C.,Ghosh, A. (deposition date: 2024-06-09, release date: 2024-09-04, Last modification date: 2024-11-13)

Primary citation

Sharma, R.,Amdare, N.P.,Ghosh, A.,Schloss, J.,Sidney, J.,Garforth, S.J.,Lopez, Y.,Celikgil, A.,Sette, A.,Almo, S.C.,DiLorenzo, T.P.
Structural and biochemical analysis of highly similar HLA-B allotypes differentially associated with type 1 diabetes.
J.Biol.Chem., 300:107702-107702, 2024

PubMed Abstract: Type 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. CD8 T cells, responding to beta cell peptides presented by class I major histocompatibility complex (MHC) molecules, are important effectors leading to beta cell elimination. Human leukocyte antigen (HLA) B*39:06, B*39:01, and B*38:01 are closely related class I MHC allotypes that nonetheless show differential association with T1D. HLA-B*39:06 is the most predisposing of all HLA class I molecules and is associated with early age at disease onset. B*39:01 is also associated with susceptibility to T1D, but to a lesser extent, though differing from B*39:06 by only two amino acids. HLA-B*38:01, in contrast, is associated with protection from the disease. Upon identifying a peptide that binds to both HLA-B*39:06 and B*39:01, we determined the respective X-ray structures of the two allotypes presenting this peptide to 1.7 Å resolution. The peptide residues available for T cell receptor contact and those serving as anchors were identified. Analysis of the F pocket of HLA-B*39:06 and B*39:01 provided an explanation for the distinct peptide C-terminus preferences of the two allotypes. Structure-based modeling of the protective HLA-B*38:01 suggested a potential reason for its peptide preferences and its reduced propensity to present 8-mer peptides compared to B*39:06. Notably, the three allotypes showed differential binding to peptides derived from beta cell autoantigens. Taken together, our findings should facilitate identification of disease-relevant candidate T cell epitopes and structure-guided therapeutics to interfere with peptide binding.

PubMed: 39173948
DOI: 10.1016/j.jbc.2024.107702

Experimental method

X-RAY DIFFRACTION (1.7 Å)