5JMO

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

Summary for 5JMO

• Entry DOI: 10.2210/pdb5jmo/pdb
• Related PRD ID: PRD_000278
• Descriptor: Furin, camelid VHH fragment, CMK-inhibitor, ... (7 entities in total)
• Functional Keywords: protease, camelid, antibody, complex, hydrolase-antibody complex, furin, hydrolase/antibody
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 132677.39

Authors

Dahms, S.O.,Than, M.E. (deposition date: 2016-04-29, release date: 2016-12-07, Last modification date: 2024-01-10)

Primary citation

Dahms, S.O.,Creemers, J.W.,Schaub, Y.,Bourenkov, G.P.,Zogg, T.,Brandstetter, H.,Than, M.E.
The structure of a furin-antibody complex explains non-competitive inhibition by steric exclusion of substrate conformers.
Sci Rep, 6:34303-34303, 2016

PubMed 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 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 Å and 2.3 Å, 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.

PubMed: 27670069
DOI: 10.1038/srep34303

Experimental method

X-RAY DIFFRACTION (1.998 Å)