2kdq: Difference between revisions
New page: '''Unreleased structure''' The entry 2kdq is ON HOLD Authors: Davidson, A.M., Leeper, T.C., Athanassiou, Z., Patora-Komisarska, K., Karn, J., Robinson, J.A., Varani, G. Description: Si... |
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The | ==Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimic of Tat protein== | ||
<StructureSection load='2kdq' size='340' side='right'caption='[[2kdq]]' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2kdq]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KDQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2KDQ FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 10 models</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DPR:D-PROLINE'>DPR</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2kdq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kdq OCA], [https://pdbe.org/2kdq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2kdq RCSB], [https://www.ebi.ac.uk/pdbsum/2kdq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2kdq ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The interaction of the HIV-1 transactivator protein Tat with its transactivation response (TAR) RNA is an essential step in viral replication and therefore an attractive target for developing antivirals with new mechanisms of action. Numerous compounds that bind to the 3-nt bulge responsible for binding Tat have been identified in the past, but none of these molecules had sufficient potency to warrant pharmaceutical development. We have discovered conformationally-constrained cyclic peptide mimetics of Tat that are specific nM inhibitors of the Tat-TAR interaction by using a structure-based approach. The lead peptides are nearly as active as the antiviral drug nevirapine against a variety of clinical isolates in human lymphocytes. The NMR structure of a peptide-RNA complex reveals that these molecules interfere with the recruitment to TAR of both Tat and the essential cellular cofactor transcription elongation factor-b (P-TEFb) by binding simultaneously at the RNA bulge and apical loop, forming an unusually deep pocket. This structure illustrates additional principles in RNA recognition: RNA-binding molecules can achieve specificity by interacting simultaneously with multiple secondary structure elements and by inducing the formation of deep binding pockets in their targets. It also provides insight into the P-TEFb binding site and a rational basis for optimizing the promising antiviral activity observed for these cyclic peptides. | |||
Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein.,Davidson A, Leeper TC, Athanassiou Z, Patora-Komisarska K, Karn J, Robinson JA, Varani G Proc Natl Acad Sci U S A. 2009 Jul 7. PMID:19584251<ref>PMID:19584251</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2kdq" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Davidson A]] | |||
[[Category: Leeper TC]] | |||
[[Category: Varani G]] | |||
Latest revision as of 11:15, 30 October 2024
Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimic of Tat proteinSimultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimic of Tat protein
Structural highlights
Publication Abstract from PubMedThe interaction of the HIV-1 transactivator protein Tat with its transactivation response (TAR) RNA is an essential step in viral replication and therefore an attractive target for developing antivirals with new mechanisms of action. Numerous compounds that bind to the 3-nt bulge responsible for binding Tat have been identified in the past, but none of these molecules had sufficient potency to warrant pharmaceutical development. We have discovered conformationally-constrained cyclic peptide mimetics of Tat that are specific nM inhibitors of the Tat-TAR interaction by using a structure-based approach. The lead peptides are nearly as active as the antiviral drug nevirapine against a variety of clinical isolates in human lymphocytes. The NMR structure of a peptide-RNA complex reveals that these molecules interfere with the recruitment to TAR of both Tat and the essential cellular cofactor transcription elongation factor-b (P-TEFb) by binding simultaneously at the RNA bulge and apical loop, forming an unusually deep pocket. This structure illustrates additional principles in RNA recognition: RNA-binding molecules can achieve specificity by interacting simultaneously with multiple secondary structure elements and by inducing the formation of deep binding pockets in their targets. It also provides insight into the P-TEFb binding site and a rational basis for optimizing the promising antiviral activity observed for these cyclic peptides. Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein.,Davidson A, Leeper TC, Athanassiou Z, Patora-Komisarska K, Karn J, Robinson JA, Varani G Proc Natl Acad Sci U S A. 2009 Jul 7. PMID:19584251[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References |
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