4DKR

Crystal structure of clade A/E 93TH057 HIV-1 gp120 core in complex with AWS-I-169

Summary for 4DKR

• Entry DOI: 10.2210/pdb4dkr/pdb
• Related: 4DKO 4DKP 4DKQ
• Descriptor: HIV-1 gp120 core, 2-acetamido-2-deoxy-beta-D-glucopyranose, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: hiv-1 gp120, clade a/e, cd4 mimic, aws-i-169, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1)
• Total number of polymer chains: 2
• Total formula weight: 84443.54

Authors

Kwon, Y.D.,LaLonde, J.M.,Jones, D.M.,Sun, A.W.,Courter, J.R.,Soeta, T.,Kobayashi, T.,Princiotto, A.M.,Wu, X.,Mascola, J.,Schon, A.,Freire, E.,Sodroski, J.,Madani, N.,Smith III, A.B.,Kwong, P.D. (deposition date: 2012-02-03, release date: 2012-05-02, Last modification date: 2024-10-30)

Primary citation

Lalonde, J.M.,Kwon, Y.D.,Jones, D.M.,Sun, A.W.,Courter, J.R.,Soeta, T.,Kobayashi, T.,Princiotto, A.M.,Wu, X.,Schon, A.,Freire, E.,Kwong, P.D.,Mascola, J.R.,Sodroski, J.,Madani, N.,Smith, A.B.
Structure-Based Design, Synthesis, and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry Inhibitors.
J.Med.Chem., 55:4382-4396, 2012

PubMed Abstract: Cellular infection by HIV-1 is initiated with a binding event between the viral envelope glycoprotein gp120 and the cellular receptor protein CD4. The CD4-gp120 interface is dominated by two hotspots: a hydrophobic gp120 cavity capped by Phe43(CD4) and an electrostatic interaction between residues Arg59(CD4) and Asp368(gp120). The CD4 mimetic small-molecule NBD-556 (1) binds within the gp120 cavity; however, 1 and related congeners demonstrate limited viral neutralization breadth. Herein, we report the design, synthesis, characterization, and X-ray structures of gp120 in complex with small molecules that simultaneously engage both binding hotspots. The compounds specifically inhibit viral infection of 42 tier 2 clades B and C viruses and are shown to be antagonists of entry into CD4-negative cells. Dual hotspot design thus provides both a means to enhance neutralization potency of HIV-1 entry inhibitors and a novel structural paradigm for inhibiting the CD4-gp120 protein-protein interaction.

PubMed: 22497421
DOI: 10.1021/jm300265j

Experimental method

X-RAY DIFFRACTION (1.8 Å)