1 Extended interaction networks with HCV protease NS3-4A substrates explain the lack of adaptive capability against protease inhibitors Georg Dultz, 1§ Tetsuro Shimakami, 2§ Markus Schneider, 3 Kazuhisa Murai, 2 Daisuke Yamane, 4 Antoine Marion, 3 Tobias M. Zeitler, 3 Claudia Stross, 1 Christian Grimm, 1 Rebecca M. Richter, 1 Katrin Bäumer, 1 MinKyung Yi, 5 Ricardo M. Biondi, 1,6 Stefan Zeuzem, 1,7 Robert Tampé, 8 Iris Antes, 3 Christian M. Lange, 1 * Christoph Welsch, 1,7# 1 Department of Internal Medicine 1, Goethe University Hospital Frankfurt, 60590 Frankfurt a.M., Germany 2 Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan 3 Technical University Munich, Center for Integrated Protein Science Munich (CIPS M ) and Department of Life Science, 85354 Freising-Weihenstephan, Germany 4 Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-Ku, Tokyo, Japan 5 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA 6 Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina 7 University Center for Infectious Diseases, University Hospital Frankfurt, 60590 Frankfurt a.M., Germany 8 Institute of Biochemistry, Biocenter and Cluster of Excellence-Macromolecular Complexes (CEF- MC), Goethe University Frankfurt, 60438 Frankfurt a.M., Germany *Present address: Department of Gastroenterology and Hepatology, University Hospital Essen and University of Duisburg-Essen, Essen, Germany. § G.D. and T.S. contributed equally to this work. # Corresponding author: Christoph Welsch E-mail: christoph.welsch@kgu.de Running Title: Structural constraints and adaptive capability in HCV NS3-4A Keywords: hepatitis C virus (HCV), serine protease (NS3-4A), structure constraints, evolution, adaptation, mitochondrial antiviral signaling protein (MAVS), protease inhibitor, resistance mutation, replicative fitness https://www.jbc.org/cgi/doi/10.1074/jbc.RA120.013898 The latest version is at JBC Papers in Press. Published on August 3, 2020 as Manuscript RA120.013898 https://www.jbc.org/cgi/doi/10.1074/jbc.RA120.013898 The latest version is at JBC Papers in Press. Published on August 3, 2020 as Manuscript RA120.013898 by guest on November 3, 2020 http://www.jbc.org/ Downloaded from