STRUCTURE OF EQUINE INFECTIOUS-ANEMIA VIRUS PROTEINASE COMPLEXED WITHAN INHIBITOR

Equine infectious anemia virus (EIAV), the causative agent of infectio us anemia in horses, is a member of the lentiviral family. The virus-e ncoded proteinase (PR) processes viral polyproteins into functional mo lecules during replication and it also cleaves viral nucleocapsid prot ein during infection. The X-ray structure of a complex of the I54G mut ant of EIAV PR with the inhibitor HBY-793 was solved at 1.8 Angstrom r esolution and refined to a crystallographic R-factor of 0.136. The mol ecule is a dimer in which the monomers are related by a crystallograph ic twofold axis. Although both the enzyme and the inhibitor are symmet ric, the interactions between the central part of the inhibitor and th e active site aspartates are asymmetric, and the inhibitor and the two flaps are partially disordered. The overall fold of EIAV PR is very s imilar to that of other retroviral proteinases. However, a novel featu re of the EIAV PR structure is the appearance of the second cr-helix i n the monomer in a position predicted by the structural template for t he family of aspartic proteinases. The parts of the EIAV PR with the h ighest resemblance to human immunodeficiency virus type 1 PR include t he substrate-binding sites; thus, the differences in the specificity o f both enzymes have to be explained by enzyme-ligand interactions at t he periphery of the active site as well.