A macrocyclic HCV NS34A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target 蛋白酶和螺旋酶残基相互作用。.pdfVIP

A macrocyclic HCV NS3/4A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target a,1 a a a a a a Nikolaus Schiering , Allan D’Arcy , Frederic Villard , Oliver Simić , Marion Kamke , Gaby Monnet , Ulrich Hassiepen , b a a c a Dmitri I. Svergun , Ruth Pulfer , Jörg Eder , Prakash Raman , and Ursula Bodendorf a Expertise Platform Proteases, Novartis Institutes for BioMedical Research, Fabrikstrasse 16, CH-4002 Basel, Switzerland; b European Molecular Biology Laboratory, Hamburg Outstation, c/o Deutsches Elektronen Synchrotron, Notkestrasse 85, D-22603 Hamburg, Germany; and c Infectious Diseases, Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139 Edited by Jennifer A. Doudna, University of California, Berkeley, CA, and approved October 21, 2011 (received for review June 30, 2011) Hepatitis C virus (HCV) infection is a global health burden with over in addition to the N-terminal protease domain (residues 1– 180) a 170 million people infected worldwide. In a significant portion of C-terminal, ATP-dependent superfamily 2 RNA helicase (resi- patients chronic hepatitis C infection leads to serious liver diseases, dues 181–631). The isolated domains of NS3, i.e., the protease including fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV and helicase domains are functional on their own. It has been NS3 protein is essential for viral polyprotein processing and RNA reported that in the full-length enzyme the NS3/4A protease replication and hence viral replication. It is composed of an N-term- enhances RNA binding