3TGQ

Crystal structure of unliganded HIV-1 clade B strain YU2 gp120 core

Summary for 3TGQ

• Entry DOI: 10.2210/pdb3tgq/pdb
• Related: 3TGR 3TGS 3TGT 3TIH
• Descriptor: HIV-1 YU2 gp120, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: hiv-1 gp120, unliganded structure, viral protein
• Biological source: Human immunodeficiency virus 1 (HIV-1)
• Total number of polymer chains: 4
• Total formula weight: 162423.58

Authors

Kwon, Y.D.,Kwong, P.D. (deposition date: 2011-08-17, release date: 2012-04-04, Last modification date: 2024-10-16)

Primary citation

Kwon, Y.D.,Finzi, A.,Wu, X.,Dogo-Isonagie, C.,Lee, L.K.,Moore, L.R.,Schmidt, S.D.,Stuckey, J.,Yang, Y.,Zhou, T.,Zhu, J.,Vicic, D.A.,Debnath, A.K.,Shapiro, L.,Bewley, C.A.,Mascola, J.R.,Sodroski, J.G.,Kwong, P.D.
Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops.
Proc.Natl.Acad.Sci.USA, 109:5663-5668, 2012

PubMed Abstract: 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.

PubMed: 22451932
DOI: 10.1073/pnas.1112391109

Experimental method

X-RAY DIFFRACTION (3.4 Å)