2KDQ

Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimic of Tat protein

2KDQ の概要

• エントリーDOI: 10.2210/pdb2kdq/pdb
• 関連するPDBエントリー: 2a9x 2ns4
• 分子名称: L-22 CYCLIC PEPTIDE, HIV-1 TAR RNA (2 entities in total)
• 機能のキーワード: peptidomimetics, peptide structure, rna recognition, immunodeficiency virus, tar rna, mimic of rna binding protein, rna binding protein-rna complex, rna binding protein/rna
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 11075.74

構造登録者

Davidson, A.,Leeper, T.C.,Varani, G. (登録日: 2009-01-14, 公開日: 2009-06-23, 最終更新日: 2024-10-30)

主引用文献

Davidson, A.,Leeper, T.C.,Athanassiou, Z.,Patora-Komisarska, K.,Karn, J.,Robinson, J.A.,Varani, G.
Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein
Proc.Natl.Acad.Sci.USA, 106:11931-11936, 2009

PubMed Abstract: 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.

PubMed: 19584251
DOI: 10.1073/pnas.0900629106

実験手法

SOLUTION NMR