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.

Cycloaddition of o‐benzoquinone imides with chiral ketene enolates derived from cinchona alkaloid catalysts is the basis of a catalytic asymmetric synthesis of 1,4‐benzoxazinones and 1,4‐benzoxazines. The resulting cycloadducts can be derivatized in situ to provide α‐amino acid products in good‐to‐excellent yields with very high enantioselectivities (see scheme; CAN=ceric ammonium nitrate, Nu=nucleophile).

Background: Extracellular regions ECL2 and the N terminus of HIV coreceptor CCR5 mediate HIV-1 entry. Results: A C-terminal CCR5 ECL2 peptide inhibits HIV-1 entry and binds to gp120 of CCR5-and CXCR4-using strains. Conclusion: The binding site for CCR5 ECL2 is conserved in CCR5-and CXCR4-using viruses. Significance: Our data provide new insights into HIV-1 gp120-CCR5 interactions that can be used for inhibitor design.