1uui

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[[Image:1uui.gif|left|200px]]
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[[Image:1uui.png|left|200px]]
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{{STRUCTURE_1uui| PDB=1uui | SCENE= }}
{{STRUCTURE_1uui| PDB=1uui | SCENE= }}
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'''NMR STRUCTURE OF A SYNTHETIC SMALL MOLECULE, RBT158, BOUND TO HIV-1 TAR RNA'''
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===NMR STRUCTURE OF A SYNTHETIC SMALL MOLECULE, RBT158, BOUND TO HIV-1 TAR RNA===
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==Overview==
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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.
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The line below this paragraph, {{ABSTRACT_PUBMED_14757049}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 14757049 is the PubMed ID number.
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{{ABSTRACT_PUBMED_14757049}}
==About this Structure==
==About this Structure==
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1UUI is a [[Single protein]] structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UUI OCA].
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1UUI is a [[Single protein]] structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UUI OCA].
==Reference==
==Reference==
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[[Category: Rna bulge]]
[[Category: Rna bulge]]
[[Category: Tar rna]]
[[Category: Tar rna]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 11:42:41 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 02:58:55 2008''

Revision as of 23:59, 28 July 2008

Image:1uui.png

Template:STRUCTURE 1uui

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

Template:ABSTRACT PUBMED 14757049

About this Structure

1UUI is a Single protein structure. Full experimental information is available from OCA.

Reference

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

Page seeded by OCA on Tue Jul 29 02:58:55 2008

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