Abstract
Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. Entry into target cells is mediated by the HIV-1 envelope (Env) glycoprotein interacting with host receptor CD4, which triggers conformational changes allowing binding to a coreceptor and subsequent membrane fusion. Small molecule or peptide CD4-mimetic drugs mimic CD4's Phe43 interaction with Env by inserting into the conserved Phe43 pocket on Env subunit gp120. Here, we present single-particle cryo-EM structures of CD4-mimetics BNM-III-170 and M48U1 bound to a BG505 native-like Env trimer plus the CD4-induced antibody 17b at 3.7 Å and 3.9 Å resolution, respectively. CD4-mimetic-bound BG505 exhibits canonical CD4-induced conformational changes including trimer opening, formation of the 4-stranded gp120 bridging sheet, displacement of the V1V2 loop, and formation of a compact and elongated gp41 HR1C helical bundle. We conclude that CD4-induced structural changes on both gp120 and gp41 Env subunits are induced by binding to the gp120 Phe43 pocket.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Binding Sites
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Biomimetic Materials / chemistry
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Biomimetic Materials / metabolism
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CD4 Antigens / antagonists & inhibitors
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CD4 Antigens / chemistry*
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CD4 Antigens / genetics
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CD4 Antigens / metabolism
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CHO Cells
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Cloning, Molecular
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Cricetulus
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Cryoelectron Microscopy
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Gene Expression
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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Guanidines / chemistry*
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Guanidines / metabolism
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HEK293 Cells
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HIV Envelope Protein gp120 / chemistry*
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HIV Envelope Protein gp120 / genetics
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HIV Envelope Protein gp120 / metabolism
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HIV Envelope Protein gp41 / chemistry*
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HIV Envelope Protein gp41 / genetics
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HIV Envelope Protein gp41 / metabolism
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HIV-1 / chemistry*
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HIV-1 / metabolism
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Humans
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Indenes / chemistry*
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Indenes / metabolism
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Models, Molecular
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Receptors, Virus / antagonists & inhibitors
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Receptors, Virus / chemistry*
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Receptors, Virus / genetics
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Receptors, Virus / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / metabolism
Substances
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BNM-III-170
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CD4 Antigens
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Guanidines
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HIV Envelope Protein gp120
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HIV Envelope Protein gp41
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Indenes
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Receptors, Virus
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Recombinant Proteins
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Small Molecule Libraries