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Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops

Author:
Kwon, Young Do, Finzi, Andrés, Wu, Xueling, Dogo-Isonagie, Cajetan, Lee, Lawrence K., Moore, Lucas R., Schmidt, Stephen D., Stuckey, Jonathan, Yang, Yongping, Zhou, Tongqing, Zhu, Jiang, Vicic, David A., Debnath, Asim K., Shapiro, Lawrence, Bewley, Carole A., Mascola, John R., Sodroski, Joseph G., Kwong, Peter D.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.15 pp. 5663-5668
ISSN:
0027-8424
Subject:
Human immunodeficiency virus 1, antibodies, crystal structure, immune response, neutralization, viruses
Abstract:
The HIV-1 envelope (Env) spike (gp1203/gp413) 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.
Agid:
421328