The development of nonpeptide fusion inhibitors through rational drug design has been hampered by the limited accessibility of the gp41 coiled coil target, which is highly hydrophobic, and the absence of structural data defining details of small molecule interactions. Here we describe a new approach for obtaining structural information on small molecules bound in the hydrophobic pocket of gp41, using a paramagnetic probe peptide which binds adjacent to the pocket along an extended coiled coil. Ligand binding in the pocket leads to paramagnetic relaxation effects or pseudocontact shifts of ligand protons. These effects are distance and/or orientation dependent, permitting determination of ligand pose in the pocket. The method is demonstrated with a fast-exchanging ligand. Multiple measurements at different coiled coil and probe peptide ratios enabled accurate determination of the NMR parameters. Use of a labeled probe peptide stabilizes an otherwise aggregation-prone coiled coil and also enables modulation of the paramagnetic effect to study ligands of various affinities. Ultimately, this technique can provide essential information for structure-based design of nonpeptide fusion inhibitors.