title: Structural Studies Revealed Active Site Distortions of Human Furin by a Small Molecule Inhibitor.
abstract: 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 1 at 1.9 Å resolution. Two molecules of inhibitor 1 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.
authors.affiliation: Protein Crystallography Group, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) , Beutenbergstr. 11, 07745 Jena, Germany.|Department of Molecular Biology, University of Salzburg , Billrothstrasse 11, A-5020 Salzburg, Austria.
authors.forename: Sven O
authors.initials: SO
authors.lastname: Dahms
authors.affiliation: Department of Chemistry, Hawaii Biotech, Inc. , Honolulu, Hawaii, United States.|MedChem ShortCut, LLC , Pearl City, Hawaii United States.
authors.forename: Guan-Sheng
authors.initials: GS
authors.lastname: Jiao
authors.affiliation: Protein Crystallography Group, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) , Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Manuel E
authors.identifier: 0000-0002-4707-9225
authors.initials: ME
authors.lastname: Than
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D045683:Furin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D043484:Proprotein Convertases; D045683:Furin