1uui | pdb_00001uui

NMR STRUCTURE OF A SYNTHETIC SMALL MOLECULE, RBT158, BOUND TO HIV-1 TAR RNA

spinqualitylabelsall models 1uui, 1 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1uui is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: P12 Related: 1uts, 1uud Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. Rational design of inhibitors of HIV-1 TAR RNA through the stabilisation of electrostatic "hot spots".,Davis B, Afshar M, Varani G, Murchie AI, Karn J, Lentzen G, Drysdale M, Bower J, Potter AJ, Starkey ID, Swarbrick T, Aboul-ela F J Mol Biol. 2004 Feb 13;336(2):343-56. PMID:14757049 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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