1UUI

NMR structure of a synthetic small molecule, rbt158, bound to HIV-1 TAR RNA

Summary for 1UUI

• Entry DOI: 10.2210/pdb1uui/pdb
• Related: 1UTS 1UUD
• Descriptor: 5'-R(*GP*GP*CP*AP*GP*AP*UP*CP*UP*GP*AP*GP*CP* CP*UP*GP*GP*GP*AP*GP*CP*UP*CP*UP*CP*UP*GP*CP*C)-3', 4-[AMINO(IMINO)METHYL]-1-[2-(3-AMMONIOPROPOXY)-5-METHOXYBENZYL]PIPERAZIN-1-IUM (2 entities in total)
• Functional Keywords: hiv-1, tar rna, drug design, ligand-rna interaction, rna bulge, inhibitor
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (CLONE 12)
• Total number of polymer chains: 1
• Total formula weight: 9630.99

Authors

Davis, B.,Afshar, M.,Varani, G.,Karn, J.,Murchie, A.I.H.,Lentzen, G.,Drysdale, M.J.,Potter, A.J.,Bower, J.,Aboul-Ela, F. (deposition date: 2003-12-19, release date: 2004-02-12, Last modification date: 2024-05-15)

Primary citation

Davis, B.,Afshar, M.,Varani, G.,Murchie, A.I.H.,Karn, J.,Lentzen, G.,Drysdale, M.J.,Bower, J.,Potter, A.J.,Aboul-Ela, F.
Rational Design of Inhibitors of HIV-1 Tar RNA Through the Stabilisation of Electrostatic "Hot Spots"
J.Mol.Biol., 336:343-, 2004

PubMed Abstract: The targeting of RNA for the design of novel anti-viral compounds has until now proceeded largely without incorporating direct input from structure-based design methodology, partly because of lack of structural data, and complications arising from substrate flexibility. We propose a paradigm to explain the physical mechanism for ligand-induced refolding of trans-activation response element (TAR RNA) from human immunodeficiency virus 1 (HIV-1). Based upon Poisson-Boltzmann analysis of the TAR structure, as bound by a peptide derived from the transcriptional activator protein, Tat, our hypothesis shows that two specific electrostatic interactions are necessary to stabilise the conformation. This result contradicts the belief that a single argininamide residue is responsible for stabilising the TAR fold, as well as the conventional wisdom that electrostatic interactions with RNA are non-specific or dominated by phosphates. We test this hypothesis by using NMR and computational methods to model the interaction of a series of novel inhibitors of the in vitro RNA-binding activities for a peptide derived from Tat. A subset of inhibitors, including the bis-guanidine compound rbt203 and its analogues, induce a conformation in TAR similar to that brought about by the protein. Comparison of the interactions of two of these ligands with the RNA and structure-activity relationships observed within the compound series, confirm the importance of the two specific electrostatic interactions in the stabilisation of the Tat-bound RNA conformation. This work illustrates how the use of medicinal chemistry and structural analysis can provide a rational basis for prediction of ligand-induced conformational change, a necessary step towards the application of structure-based methods in the design of novel RNA or protein-binding drugs.

PubMed: 14757049
DOI: 10.1016/J.JMB.2003.12.046

Experimental method

SOLUTION NMR