4DKQ: Crystal Structure Of Clade AE 93TH057 HIV-1 Gp120 Core In Complex With Dmj-I-228

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.
PDB ID: 4DKQDownload
MMDB ID: 99245
PDB Deposition Date: 2012/2/3
Updated in MMDB: 2012/06
Experimental Method:
x-ray diffraction
Resolution: 1.89  Å
Source Organism:
Similar Structures:
Biological Unit for 4DKQ: monomeric; determined by author and by software (PISA)
Molecular Components in 4DKQ
Label Count Molecule
Protein (1 molecule)
Clade AE 93th057 Hiv-1 Gp120 Core
Molecule annotation
Chemicals (13 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB