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

Journal Article · Mon Mar 04 04:00:00 EST 2013 · Proc. Natl. Acad. Sci. USA

DOI:https://doi.org/10.1073/pnas.1112391109· OSTI ID:1041327

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 ^[1]

---

1. Harvard-Med

The HIV-1 envelope (Env) spike (gp120{sub 3}/gp41{sub 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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: NIH
• OSTI ID: 1041327
• Journal Information: Proc. Natl. Acad. Sci. USA, Journal Name: Proc. Natl. Acad. Sci. USA Journal Issue: (15) ; 04, 2012 Vol. 109; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBODIES
CAPACITY
CRYSTAL STRUCTURE
CRYSTALLOGRAPHY
INACTIVATION
REGULATIONS
RESTRAINTS
THERMODYNAMICS