2L8H

Chemical probe bound to HIV TAR RNA

Summary for 2L8H

• Entry DOI: 10.2210/pdb2l8h/pdb
• NMR Information: BMRB: 17408
• Descriptor: HIV TAR RNA, ARGININE, 4-methoxynaphthalen-2-amine (3 entities in total)
• Functional Keywords: rna
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 9655.98

Authors

Davidson, A.,Begley, D.,Lau, C.,Varani, G. (deposition date: 2011-01-12, release date: 2011-03-23, Last modification date: 2024-05-15)

Primary citation

Davidson, A.,Begley, D.W.,Lau, C.,Varani, G.
A Small-Molecule Probe Induces a Conformation in HIV TAR RNA Capable of Binding Drug-Like Fragments.
J.Mol.Biol., 410:984-996, 2011

PubMed Abstract: The HIV-1 transactivation response (TAR) element-Tat interaction is a potentially valuable target for treating HIV infection, but efforts to develop TAR-binding antiviral drugs have not yet yielded a successful candidate for clinical development. In this work, we describe a novel approach toward screening fragments against RNA that uses a chemical probe to target the Tat-binding region of TAR. This probe fulfills two critical roles in the screen: by locking the RNA into a conformation capable of binding other fragments, it simultaneously allows the identification of proximal binding fragments by ligand-based NMR. Using this approach, we have discovered six novel TAR-binding fragments, three of which were docked relative to the probe-RNA structure using experimental NMR restraints. The consistent orientations of functional groups in our data-driven docked structures and common electrostatic properties across all fragment leads reveal a surprising level of selectivity by our fragment-sized screening hits. These models further suggest linking strategies for the development of higher-affinity lead compounds for the inhibition of the TAR-Tat interaction.

PubMed: 21763501
DOI: 10.1016/j.jmb.2011.03.039

Experimental method

SOLUTION NMR