6K60

Structural and functional basis for HLA-G isoform recognition of immune checkpoint receptor LILRBs

Summary for 6K60

• Entry DOI: 10.2210/pdb6k60/pdb
• Descriptor: HLA class I histocompatibility antigen, alpha chain G, Beta-2-microglobulin, Peptide from Histone H2A.J, ... (5 entities in total)
• Functional Keywords: hla class i, hlag, lilrb1/ilt2, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 135365.46

Authors

Kuroki, K.,Matsubara, H.,Kanda, R.,Miyashita, N.,Shiroishi, M.,Fukunaga, Y.,Kamishikiryo, J.,Fukunaga, A.,Hirose, K.,Sugita, Y.,Kita, S.,Ose, T.,Maenaka, K. (deposition date: 2019-05-31, release date: 2019-11-27, Last modification date: 2023-11-22)

Primary citation

Kuroki, K.,Matsubara, H.,Kanda, R.,Miyashita, N.,Shiroishi, M.,Fukunaga, Y.,Kamishikiryo, J.,Fukunaga, A.,Fukuhara, H.,Hirose, K.,Hunt, J.S.,Sugita, Y.,Kita, S.,Ose, T.,Maenaka, K.
Structural and Functional Basis for LILRB Immune Checkpoint Receptor Recognition of HLA-G Isoforms.
J Immunol., 203:3386-3394, 2019

PubMed Abstract: Human leukocyte Ig-like receptors (LILR) LILRB1 and LILRB2 are immune checkpoint receptors that regulate a wide range of physiological responses by binding to diverse ligands, including HLA-G. HLA-G is exclusively expressed in the placenta, some immunoregulatory cells, and tumors and has several unique isoforms. However, the recognition of HLA-G isoforms by LILRs is poorly understood. In this study, we characterized LILR binding to the β2-microglobulin (β2m)-free HLA-G1 isoform, which is synthesized by placental trophoblast cells and tends to dimerize and multimerize. The multimerized β2m-free HLA-G1 dimer lacked detectable affinity for LILRB1, but bound strongly to LILRB2. We also determined the crystal structure of the LILRB1 and HLA-G1 complex, which adopted the typical structure of a classical HLA class I complex. LILRB1 exhibits flexible binding modes with the α3 domain, but maintains tight contacts with β2m, thus accounting for β2m-dependent binding. Notably, both LILRB1 and B2 are oriented at suitable angles to permit efficient signaling upon complex formation with HLA-G1 dimers. These structural and functional features of ligand recognition by LILRs provide novel insights into their important roles in the biological regulations.

PubMed: 31694909
DOI: 10.4049/jimmunol.1900562

Experimental method

X-RAY DIFFRACTION (3.149 Å)