title: Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops.
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.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Young Do
authors.initials: YD
authors.lastname: Kwon
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.forename: Cajetan
authors.initials: C
authors.lastname: Dogo-Isonagie
authors.forename: Lawrence K
authors.initials: LK
authors.lastname: Lee
authors.forename: Lucas R
authors.initials: LR
authors.lastname: Moore
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stuckey
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Tongqing
authors.initials: T
authors.lastname: Zhou
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.forename: David A
authors.initials: DA
authors.lastname: Vicic
authors.forename: Asim K
authors.initials: AK
authors.lastname: Debnath
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.forename: Carole A
authors.initials: CA
authors.lastname: Bewley
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Sodroski
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism*; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D008024:Ligands; D012996:Solutions