Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand

Area of Science:

• Immunology
• Structural Biology
• Molecular Interactions

Background:

• Natural killer (NK) cell receptors mediate target cell lysis by recognizing class I MHC molecules.
• Understanding these interactions is key to deciphering immune surveillance and response.

Purpose of the Study:

• To determine the crystal structure of the human NK cell receptor KIR2DL2 in complex with its ligand HLA-Cw3 and peptide.
• To elucidate the molecular basis of KIR-HLA interactions and allotype specificity.

Main Methods:

• X-ray crystallography to obtain the high-resolution structure of the KIR2DL2-HLA-Cw3-peptide complex.
• Site-directed mutagenesis to investigate the role of specific residues and salt bridges in binding affinity.

Main Results:

• The crystal structure shows KIR2DL2 binds HLA-Cw3 orthogonally, contacting the peptide at positions 7 and 8.
• Charge complementarity is dominant at the KIR/HLA interface, with specific salt bridges critical for binding.
• A hydrogen bond between KIR2DL2 (Lys 44) and HLA-Cw3 (Asn 80) confers allotype specificity.
• Peptide residue at position 8 must be smaller than valine for KIR contact.
• Observed receptor-ligand aggregation may mimic immune synapse formation.

Conclusions:

• The structure provides a detailed molecular understanding of KIR2DL2-HLA-Cw3 recognition.
• Key interactions, including charge complementarity and specific hydrogen bonds, dictate binding affinity and specificity.
• Findings offer insights into NK cell activation and potential therapeutic targets.