2KDQ
Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimic of Tat protein
Summary for 2KDQ
| Entry DOI | 10.2210/pdb2kdq/pdb |
| Related | 2a9x 2ns4 |
| Descriptor | L-22 CYCLIC PEPTIDE, HIV-1 TAR RNA (2 entities in total) |
| Functional Keywords | peptidomimetics, peptide structure, rna recognition, immunodeficiency virus, tar rna, mimic of rna binding protein, rna binding protein-rna complex, rna binding protein/rna |
| Total number of polymer chains | 2 |
| Total formula weight | 11075.74 |
| Authors | Davidson, A.,Leeper, T.C.,Varani, G. (deposition date: 2009-01-14, release date: 2009-06-23, Last modification date: 2024-10-30) |
| Primary citation | 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 Cited by 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: 19584251DOI: 10.1073/pnas.0900629106 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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