Structural Studies Revealed Active Site Distortions of Human Furin by a Small Molecule Inhibitor

Proprotein convertases (PCs) represent highly selective serine proteases that activate their substrates upon proteolytic cleavage. Their inhibition is a promising strategy for the treatment of several pathologies including cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases. Here, we present the first experimental complex of furin with a non-substrate-like small molecule inhibitor, and the X-ray structure of the enzyme complexed to the small molecule inhibitor <b>1</b> at 1.9 Å resolution. Two molecules of inhibitor <b>1</b> were found to interact with furin. One is anchored at the S4 pocket of the enzyme and interferes directly with the conformation and function of the catalytic triade; the other molecule shows weaker binding and interacts with a distant, less conserved region of furin. The observed binding modes represent a new inhibition strategy of furin and imply the possibility to attain specificity among the PCs providing an innovative starting point of structure guided inhibitor development for furin