a symmetric region of the hiv-1 integrase dimerization interface is essential for viral replication对称区域的hiv - 1整合酶二聚作用界面是病毒复制所必需的.pdfVIP

A Symmetric Region of the HIV-1 Integrase Dimerization Interface Is Essential for Viral Replication 1 2 2 1 2 Erik Serrao , Wannes Thys , Jonas Demeulemeester , Laith Q. Al-Mawsawi , Frauke Christ , 2 1 Zeger Debyser , Nouri Neamati * 1 Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America, 2 Laboratory for Molecular Virology and Gene Therapy, Division of Molecular Medicine, Katholieke Universiteit Leuven, Flanders, Belgium Abstract HIV-1 integrase (IN) is an important target for contemporary antiretroviral drug design research. Historically, efforts at inactivating the enzyme have focused upon blocking its active site. However, it has become apparent that new classes of allosteric inhibitors will be necessary to advance the antiretroviral field in light of the emergence of viral strains resistant to contemporary clinically used IN drugs. In this study we have characterized the importance of a close network of IN residues, distant from the active site, as important for the obligatory multimerization of the enzyme and viral replication as a whole. Specifically, we have determined that the configuration of six residues within a highly symmetrical region at the IN dimerization interface, composed of a four-tiered aromatic interaction flanked by two salt bridges, significantly contributes to proper HIV-1 replication. Additionally, we have utilized a quantitative luminescence assay to examine IN oligomerization and have determined that there is a very low tolerance for ami