The HIV-1 envelope (Env) spike (gp120 3 /gp41 3 ) undergoes considerable structural rearrangements to mediate virus entry into cells and to evade the host immune response. Engagement of CD4, the primary human receptor, fixes a particular conformation and primes Env for entry. The CD4-bound state, however, is prone to spontaneous inactivation and susceptible to antibody neutralization. How does unliganded HIV-1 maintain CD4-binding capacity and regulate transitions to the CD4-bound state? To define this mechanistically, we determined crystal structures of unliganded core gp120 from HIV-1 clades B, C, and E. Notably, all of these unliganded HIV-1 structures resembled the CD4-bound state. Conformational fixation with ligand selection and thermodynamic analysis of full-length and core gp120 interactions revealed that the tendency of HIV-1 gp120 to adopt the CD4-bound conformation was restrained by the V1/V2- and V3-variable loops. In parallel, we determined the structure of core gp120 in complex with the small molecule, NBD-556, which specifically recognizes the CD4-bound conformation of gp120. Neutralization by NBD-556 indicated that Env spikes on primary isolates rarely assume the CD4-bound conformation spontaneously, although they could do so when quaternary restraints were loosened. Together, the results suggest that the CD4-bound conformation represents a “ground state” for the gp120 core, with variable loop and quaternary interactions restraining unliganded gp120 from “snapping” into this conformation. A mechanism of control involving deformations in unliganded structure from a functionally critical state (e.g., the CD4-bound state) provides advantages in terms of HIV-1 Env structural diversity and resistance to antibodies and inhibitors, while maintaining elements essential for entry.

The ability of the terpyridine ligand to stabilize alkyl complexes of nickel has been central in obtaining a fundamental understanding of the key processes involved in alkyl-alkyl cross-coupling reactions. Here, mechanistic studies using isotopically labeled (TMEDA)NiMe(2) (TMEDA = N,N,N',N'-tetramethylethylenediamine) have shown that an important catalyst in alkyl-alkyl cross-coupling reactions, (tpy')NiMe (2b, tpy' = 4,4',4' '-tri-tert-butylterpyridine), is not produced via a mechanism that involves the formation of methyl radicals. Instead, it is proposed that (terpyridine)NiMe complexes arise via a comproportionation reaction between a Ni(II)-dimethyl species and a Ni(0) fragment in solution upon addition of a terpyridine ligand to (TMEDA)NiMe(2). EPR and DFT studies on the paramagnetic (terpyridine)NiMe (2a) both suggest that the unpaired electron resides heavily on the terpyridine ligand and that the proper electronic description of this nickel complex is a Ni(II)-methyl cation bound to a reduced terpyridine ligand. Thus, an important consequence of these results is that alkyl halide reduction by (terpyridine)NiR(alkyl) complexes appears to be substantially ligand based. A comprehensive survey investigating the catalytic reactivity of related ligand derivatives suggests that electronic factors only moderately influence reactivity in the terpyridine-based catalysis and that the most dramatic effects arise from steric and solubility factors.

The first examples of isolable and structurally characterized Cu(I)-CF3 complexes are reported. N-Heterocyclic carbene (NHC)-supported copper tert-butoxide complexes reacted with Me3Si-CF3 to afford new (NHC)Cu-CF3 complexes whose structures were dependent on whether or not the C4-C5 positions of the five-membered NHC rings were saturated. In situ generated (SIiPr)Cu-CF3 cleanly transferred its trifluoromethyl group to a number of organic halides under mild conditions.