2.8 angstrom resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity

TRAIL is a newly identified cytokine belonging to the large tumor necrosis factor (TNF) family. TRAIL is a novel molecule inducing apoptosis in a wide variety of tumor cells but not in normal cells. To help in elucidating its biological roles and designing mutants with improved therapeutic potential , we have determined the crystal structure of human TRAIL. The structure re veals that a unique frame insertion of 12-16 amino acids adopts a salient l oop structure penetrating into the receptor-binding site. The loop drastica lly alters the common receptor-binding surface of the TNF family most likel y for the specific recognition of cognate partners. A structure-based mutag enesis study demonstrates a critical role of the insertion loop in the cyto toxic activity of TRAIL.