5HLF

STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE In COMPLEX WITH A 38-MER HAIRPIN TEMPLATE-PRIMER DNA APTAMER AND AN ALPHA-CARBOXYPHOSPHONATE INHIBITOR

Summary for 5HLF

• Entry DOI: 10.2210/pdb5hlf/pdb
• Related: 3V4I 4R5P 5D3G 5HP1
• Related PRD ID: PRD_900003
• Descriptor: HIV-1 REVERSE TRANSCRIPTASE P66 SUBUNIT, HIV-1 REVERSE TRANSCRIPTASE P51 SUBUNIT, DNA (38-MER), ... (9 entities in total)
• Functional Keywords: dna aptamer, 2-o-methylcytidine, p51, p66, transferase, ncrti, nucleotide competing, inhibitor, transferase-inhibitor-dna complex, transferase/inhibitor/dna
• Biological source: Human immunodeficiency virus type 1 group M subtype B (isolate BH10) (HIV-1); More
• Total number of polymer chains: 6
• Total formula weight: 257379.49

Authors

Das, K.,Arnold, E. (deposition date: 2016-01-15, release date: 2016-02-10, Last modification date: 2023-09-27)

Primary citation

Mullins, N.D.,Maguire, N.M.,Ford, A.,Das, K.,Arnold, E.,Balzarini, J.,Maguire, A.R.
Exploring the role of the alpha-carboxyphosphonate moiety in the HIV-RT activity of alpha-carboxy nucleoside phosphonates.
Org.Biomol.Chem., 14:2454-2465, 2016

PubMed Abstract: As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 Å resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2.

PubMed: 26813581
DOI: 10.1039/c5ob02507a

Experimental method

X-RAY DIFFRACTION (2.95 Å)