6PSA

PIE12 D-PEPTIDE AGAINST HIV ENTRY (IN COMPLEX WITH IQN17 Q577R RESISTANCE MUTANT)

Summary for 6PSA

• Entry DOI: 10.2210/pdb6psa/pdb
• Descriptor: PIE12 D-peptide, IQN17, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: hiv, helix, hiv entry inhibitor, iqn17 pie12, d-peptide inhibitor, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: synthetic construct; More
• Total number of polymer chains: 2
• Total formula weight: 7642.74

Authors

Hill, C.P.,Whitby, F.G.,Kay, M.,Weinstock, M. (deposition date: 2019-07-12, release date: 2020-02-05)

Primary citation

Smith, A.R.,Weinstock, M.T.,Siglin, A.E.,Whitby, F.G.,Francis, J.N.,Hill, C.P.,Eckert, D.M.,Root, M.J.,Kay, M.S.
Characterization of resistance to a potent D-peptide HIV entry inhibitor.
Retrovirology, 16:28-28, 2019

PubMed Abstract: PIE12-trimer is a highly potent D-peptide HIV-1 entry inhibitor that broadly targets group M isolates. It specifically binds the three identical conserved hydrophobic pockets at the base of the gp41 N-trimer with sub-femtomolar affinity. This extremely high affinity for the transiently exposed gp41 trimer provides a reserve of binding energy (resistance capacitor) to prevent the viral resistance pathway of stepwise accumulation of modest affinity-disrupting mutations. Such modest mutations would not affect PIE12-trimer potency and therefore not confer a selective advantage. Viral passaging in the presence of escalating PIE12-trimer concentrations ultimately selected for PIE12-trimer resistant populations, but required an extremely extended timeframe (> 1 year) in comparison to other entry inhibitors. Eventually, HIV developed resistance to PIE12-trimer by mutating Q577 in the gp41 pocket.

PubMed: 31640718
DOI: 10.1186/s12977-019-0489-7

Experimental method

X-RAY DIFFRACTION (1.3 Å)