Structure of a V3-Containing HIV-1 gp120 Core

Huang, Chien‐Yi; Tang, Min; Zhang, Meiyun; Majeed, Shahzad; Montabana, Elizabeth; Stanfield, Robyn L.; Dimitrov, Dimiter S.; Korber, Bette T.; Sodroski, Joseph; Wilson, Ian A.; Wyatt, Richard T.; Kwong, Peter D.

doi:10.1126/science.1118398

Cited by 676 publications

(831 citation statements)

References 35 publications

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“…HIV-1 gp120 trimers dock to the Nterminal domain of the primary viral receptor, CD4, undergoing a profound conformational change whose details have been evinced from the structure of CD4-bound HIV-1 gp120 and unbound SIV gp120 [2,3]. Consequently, gp120 exposes the binding site for the coreceptor, CCR5 or CXCR4 [1].…”

Section: Introductionmentioning

confidence: 99%

Critical role of the N-loop and β1-strand hydrophobic clusters of RANTES-derived peptides in anti-HIV activity

Vangelista¹,

Longhi

Sironi³

et al. 2006

Biochemical and Biophysical Research Communications

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HIV initiates its infectious cycle by docking to CD4 and a chemokine receptor, most commonly CCR5. RANTES, a natural CCR5 ligand, is a potent inhibitor of HIV-1. Despite the lack of structural information on the RANTES-CCR5 complex, determinants of HIV blockade were previously identified within the RANTES N-loop and β1-strand regions. A prototype N-loop/β1-strand peptide, named R11-29, contains two terminal hydrophobic stretches separated by a central hydrophilic region. Here, the role of the terminal hydrophobic clusters was investigated by means of amino acid substitutions or deletions. Most hydrophobic residues in these clusters were shown to be fundamental for the anti-HIV activity. However, increasing the hydrophobicity of the two clusters using nonnatural amino acids did not significantly improve the potency of the peptides. These results may provide instrumental knowledge for the rational design of RANTES-derivative molecules with increased anti-HIV activity.

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Section: Introductionmentioning

confidence: 99%

Critical role of the N-loop and β1-strand hydrophobic clusters of RANTES-derived peptides in anti-HIV activity

Vangelista¹,

Longhi

Sironi³

et al. 2006

Biochemical and Biophysical Research Communications

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“…The interaction between the Env gp120 subunit and CCR5 involves two structural elements: a gp120 site comprising the CD4-induced, 4-stranded bridging sheet region and the base of V3 recognizes the CCR5 N terminus (NT), while residues near the V3 tip interact with the second extracellular loop (ECL2) (4,5). Small-molecule CCR5 inhibitors such as the licensed drug maraviroc (MVC) and the experimental compound vicriviroc (VVC) impair this interaction by a predominantly noncompetitive mechanism.…”

mentioning

confidence: 99%

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Berro

Yasmeen

Abrol

et al. 2013

J Virol

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Small-molecule CCR5 inhibitors such as vicriviroc (VVC) and maraviroc (MVC) are allosteric modulators that impair HIV-1 entry by stabilizing a CCR5 conformation that the virus recognizes inefficiently. Viruses resistant to these compounds are able to bind the inhibitor-CCR5 complex while also interacting with the free coreceptor. CCR5 also interacts intracellularly with G proteins, as part of its signal transduction functions, and this process alters its conformation. Here we investigated whether the action of VVC against inhibitor-sensitive and -resistant viruses is affected by whether or not CCR5 is coupled to G proteins such as G␣ i . Treating CD4 ؉ T cells with pertussis toxin to uncouple the G␣ i subunit from CCR5 increased the potency of VVC against the sensitive viruses and revealed that VVC-resistant viruses use the inhibitor-bound form of G␣ i -coupled CCR5 more efficiently than they use uncoupled CCR5. Supportive evidence was obtained by expressing a signaling-deficient CCR5 mutant with an impaired ability to bind to G proteins, as well as two constitutively active mutants that activate G proteins in the absence of external stimuli. The implication of these various studies is that the association of intracellular domains of CCR5 with the signaling machinery affects the conformation of the external and transmembrane domains and how they interact with small-molecule inhibitors of HIV-1 entry.

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“…CD4 binding appears to induce the formation of the bridging sheet domain itself, as the two pairs of b-sheets are spatially separated in a crystal structure of the unbound core of SIV gp120 but come together to form a four-stranded sheet in the CD4-bound conformation [79,81,82]. Additional changes in gp120 occur with CD4 binding, including movement of the V1/V2 and V3 loop domains.…”

Section: Mechanism Of Action Of Gp120mentioning

confidence: 99%

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

Teixeira

Gomes

et al. 2011

European Journal of Medicinal Chemistry

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Structure of a V3-Containing HIV-1 gp120 Core

Cited by 676 publications

References 35 publications

Critical role of the N-loop and β1-strand hydrophobic clusters of RANTES-derived peptides in anti-HIV activity

Critical role of the N-loop and β1-strand hydrophobic clusters of RANTES-derived peptides in anti-HIV activity

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

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