STRUCTURE OF AN INTERLEUKIN-1-BETA MUTANT WITH REDUCED BIOACTIVITY SHOWS MULTIPLE SUBTLE CHANGES IN CONFORMATION THAT AFFECT PROTEIN-PROTEIN RECOGNITION

Site-specific mutagenesis was used to obtain the human interleukin-1be ta mutant protein with glycine substituted for threonine at position 9 (IL-1beta Thr9Gly). The mutant maintains receptor binding but exhibit s significantly reduced biological activity. The crystal structure of IL-1beta Thr9Gly has been determined at 2.4-angstrom resolution by mol ecular replacement techniques and refined to a crystallographic R-fact or of 19.0%. IL-1beta Thr9Gly crystallizes in a different space group (P6(5)22) than does native IL-1beta (P4(3)); thus the molecules pack d ifferently. Their overall structure is similar, nevertheless, with bot h composed of 153 amino acids which form 12 antiparallel beta-strands. However, significant conformational differences both close to and far from the site of the mutation may explain the mutant's altered proper ties.