9LRH

Killer immunoglobulin receptor KIR2DL2 in complex with KIR2DL2_KIR2DL2/3 agonist 61-scFv

Summary for 9LRH

• Entry DOI: 10.2210/pdb9lrh/pdb
• Related: 9LRA 9LRF
• Descriptor: Killer cell immunoglobulin-like receptor 2DL2, KIR2DL2_KIR2DL2/3 agonist 61 scFV, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: kir, natural killer receptor, inhibitory receptor, 2dl2, immunoglobulin, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 76402.10

Authors

Nishikawa, Y. (deposition date: 2025-01-31, release date: 2025-10-15)

Primary citation

Hiura, S.,Kuwasaki, Y.,Nishikawa, Y.,Kimura, T.,Yoshida, S.,Nakayama, M.,Makino, T.,Ueno, S.
Selective agonists of KIR and NKG2A to evade missing self response of natural killer cells.
Sci Rep, 15:33550-33550, 2025

PubMed Abstract: Immune rejection is one of the most serious challenges in allogeneic transplantation, including allogeneic induced pluripotent stem cell (allo-iPSC)-derived cell therapy. Beta-2-Microglobulin gene-knockout, human leukocyte antigen (HLA) class I-deficient iPSCs can evade immune rejection by host T cells, which occurs due to HLA mismatches. However, natural killer (NK) cells recognize HLA class Ⅰ-deficient cells and reject them, which is known as the missing-self response. Introducing chimeric HLA-E protein to HLA class Ⅰ-deficient iPSCs suppresses the missing-self response of NK cells expressing the inhibitory receptor NKG2A; however, technology to suppress NKG2A-negative NK cells is still required. Here, we developed novel agonists for the other inhibitory receptor, killer immunoglobulin receptor (KIR), on NK cells. We found that antibodies that bind to activating KIR enhance NK cell activation and developed selective agonists for inhibitory KIRs (KIR2DL1, KIR2DL2/3, and KIR3DL1). Introducing these selective inhibitory KIR agonists on T cells and HLA class Ⅰ-deficient iPSCs allowed them to evade immune rejection by NK cells. Additionally, we identified an NKG2A-selective agonist as an alternative to chimeric HLA-E, which stimulates the activating receptor NKG2C. This technology enhances immune tolerance in allo-iPSCs and facilitates the development of various iPSC-derived regenerative medicines.

PubMed: 41023081
DOI: 10.1038/s41598-025-18394-z

Experimental method

X-RAY DIFFRACTION (3.4 Å)