4I53

Crystal structure of clade C1086 HIV-1 gp120 core in complex with DMJ-II-121

Summary for 4I53

• Entry DOI: 10.2210/pdb4i53/pdb
• Descriptor: HIV-1 glycoprotein, amino({[(1R,2R)-1-({[(4-chloro-3-fluorophenyl)amino](oxo)acetyl}amino)-2,3-dihydro-1H-inden-2-yl]methyl}amino)methanimi nium, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: hiv, gp120, entry inhibitor, dmj-ii-121, cd4-mimetic, viral protein-inhibitor complex, c1086, extracellular, viral protein/inhibitor
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS TYPE 1
• Total number of polymer chains: 2
• Total formula weight: 83242.75

Authors

Le-Khac, M.,Hendrickson, W.A. (deposition date: 2012-11-28, release date: 2013-05-29, Last modification date: 2024-11-27)

Primary citation

Lalonde, J.M.,Le-Khac, M.,Jones, D.M.,Courter, J.R.,Park, J.,Schon, A.,Princiotto, A.M.,Wu, X.,Mascola, J.R.,Freire, E.,Sodroski, J.,Madani, N.,Hendrickson, W.A.,Smith, A.B.
Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-Ray and Thermodynamic Characterization.
ACS Med Chem Lett, 4:338-343, 2013

PubMed Abstract: The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a sub-micromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. thermodynamic signatures indicate a binding preference for the ()-over the ()-enantiomer. The crystal structure of the small molecule-gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4:gp120 interface is an effective tactic to enhance the neutralization potency of small molecule HIV-1 entry inhibitors.

PubMed: 23667716
DOI: 10.1021/ml300407y

Experimental method

X-RAY DIFFRACTION (2.5002 Å)