The structure of an HIV-1 specific cell entry inhibitor in complex with the HIV-1 gp41 trimeric core

The three-dimensional structure of the complex between an HIV-1 cell-entry inhibitor selected from screening a combinatorial library of non-natural bu ilding blocks and the central, trimeric, coiled-coil core of HIV-1 gp41 has been determined by Xray crystallography. The biased combinatorial library was designed to identify ligands binding in nonpolar pockets on the surface of the coiled-coil core of gp41. The crystal structure shows that the non- peptide moiety of the inhibitor binds to the targeted cavity in two differe nt binding modes. This result suggests a strategy for increasing inhibitor potency by use of a second-generation combinatorial library designed to giv e simultaneous occupancy of both binding sites. (C) 2000 Elsevier Science L td. All rights reserved.