Crystal structure of the human 4-1BB/4-1BBL complex

Area of Science:

• Structural biology
• Immunology
• Protein structure determination

Background:

• 4-1BBL is a TNF superfamily ligand crucial for T cell and NK cell immunomodulation.
• Agonists targeting the 4-1BB receptor are promising immunotherapy agents.
• Previous structural data suggested a unique trimer assembly for human 4-1BBL.

Purpose of the Study:

• To determine the crystal structure of the human 4-1BB/4-1BBL complex.
• To clarify the structural features of 4-1BBL and its complex with 4-1BB.
• To provide insights into the structure-function relationships within the TNF/TNFR superfamily.

Main Methods:

• X-ray crystallography at 2.4-Å resolution.
• Protein structure determination and analysis.
• Mutational analysis to validate structural findings.

Main Results:

• The crystal structure revealed that 4-1BBL forms a canonical bell-shaped trimer, not the previously reported unique assembly.
• The structure of 4-1BB and the 4-1BB/4-1BBL complex were also largely canonical.
• Mutational data supported the biologically relevant structure of 4-1BBL presented in this study.

Conclusions:

• The human 4-1BB/4-1BBL complex adopts a canonical structure within the TNF superfamily.
• The previously reported unique structure of 4-1BBL appears not to be biologically relevant.
• This study enhances the structural understanding of the 4-1BB/4-1BBL system and the broader TNF/TNFR superfamily.