5jmo | pdb_00005jmo

X-ray structure of furin in complex with the inhibitory antibody Nb14

spinqualitylabelsall models 5jmo, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5jmo is a 6 chain structure with sequence from Arabian camel and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, NA, NAG NonStd Res: 0QE, AR7, DKA Gene: FURIN, FUR, PACE, PCSK3 (HUMAN) Activity: Furin, with EC number 3.4.21.75 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [FURIN_HUMAN] Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif. Publication Abstract from PubMed 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 cancer and infectious diseases. Inhibitory camelid antibodies were developed, targeting the prototypical PC furin. Kinetic analyses of them revealed an enigmatic non-competitive mechanism, affecting the inhibition of large proprotein-like but not small peptidic substrates. Here we present the crystal structures of furin in complex with the antibody Nb14 and of free Nb14 at resolutions of 2.0 A and 2.3 A, respectively. Nb14 binds at a site distant to the substrate binding pocket to the P-domain of furin. Interestingly, no major conformational changes were observed upon complex formation, neither for the protease nor for the antibody. Inhibition of furin by Nb14 is instead explained by steric exclusion of specific substrate conformers, explaining why Nb14 inhibits the processing of bulky protein substrates but not of small peptide substrates. This mode of action was further supported by modelling studies with the ternary factor X-furin-antibody complex and a mutation that disrupted the interaction interface between furin and the antibody. The observed binding mode of Nb14 suggests a novel approach for the development of highly specific antibody-based proprotein convertase inhibitors. The structure of a furin-antibody complex explains non-competitive inhibition by steric exclusion of substrate conformers.,Dahms SO, Creemers JW, Schaub Y, Bourenkov GP, Zogg T, Brandstetter H, Than ME Sci Rep. 2016 Sep 27;6:34303. doi: 10.1038/srep34303. PMID:27670069 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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