6D2U

Solution structure of a ultra-high affinity macrocycle bound to HIV-1 TAR RNA


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 200 
  • Conformers Submitted: 10 
  • Selection Criteria: structures with the lowest energy 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

An ultra-high affinity ligand of HIV-1 TAR reveals the RNA structure recognized by P-TEFb.

Shortridge, M.D.Wille, P.T.Jones, A.N.Davidson, A.Bogdanovic, J.Arts, E.Karn, J.Robinson, J.A.Varani, G.

(2019) Nucleic Acids Res 47: 1523-1531

  • DOI: 10.1093/nar/gky1197
  • Primary Citation of Related Structures:  
    6D2U

  • PubMed Abstract: 
  • The HIV-1 trans-activator protein Tat binds the trans-activation response element (TAR) to facilitate recruitment of the super elongation complex (SEC) to enhance transcription of the integrated pro-viral genome. The Tat-TAR interaction is critical for viral replication and the emergence of the virus from the latent state, therefore, inhibiting this interaction has long been pursued to discover new anti-viral or latency reversal agents ...

    The HIV-1 trans-activator protein Tat binds the trans-activation response element (TAR) to facilitate recruitment of the super elongation complex (SEC) to enhance transcription of the integrated pro-viral genome. The Tat-TAR interaction is critical for viral replication and the emergence of the virus from the latent state, therefore, inhibiting this interaction has long been pursued to discover new anti-viral or latency reversal agents. However, discovering active compounds that directly target RNA with high affinity and selectivity remains a significant challenge; limiting pre-clinical development. Here, we report the rational design of a macrocyclic peptide mimic of the arginine rich motif of Tat, which binds to TAR with low pM affinity and 100-fold selectivity against closely homologous RNAs. Despite these unprecedented binding properties, the new ligand (JB181) only moderately inhibits Tat-dependent reactivation in cells and recruitment of positive transcription elongation factor (P-TEFb) to TAR. The NMR structure of the JB181-TAR complex revealed that the ligand induces a structure in the TAR loop that closely mimics the P-TEFb/Tat1:57/AFF4/TAR complex. These results strongly suggest that high-affinity ligands which bind the UCU bulge are not likely to inhibit recruitment of the SEC and suggest that targeting of the TAR loop will be an essential feature of effective Tat inhibitors.


    Organizational Affiliation

    Department of Chemistry, University of Washington, Seattle, Washington 98195-1700.



Macromolecules

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
DAB-VAL-ARG-THR-ARG-LYS-GLY-ARG-ARG-ILE-NOR-ILE-DPR-PROA14synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Protein Feature View
Expand
  • Reference Sequence
Find similar nucleic acids by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChainsLengthOrganismImage
RNA (29-MER)B 29synthetic construct
Protein Feature View
Expand
  • Reference Sequence
Small Molecules
Modified Residues  2 Unique
IDChainsTypeFormula2D DiagramParent
4J5
Query on 4J5
A L-PEPTIDE LINKINGC5 H13 N4 O2ARG
DAB
Query on DAB
A L-PEPTIDE LINKINGC4 H10 N2 O2ALA
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 200 
  • Conformers Submitted: 10 
  • Selection Criteria: structures with the lowest energy 
  • OLDERADO: 6D2U Olderado

Structure Validation

View Full Validation Report




Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States5R01GM110569

Revision History  (Full details and data files)

  • Version 1.0: 2018-12-12
    Type: Initial release
  • Version 1.1: 2019-07-03
    Changes: Data collection, Database references
  • Version 1.2: 2020-01-01
    Changes: Author supporting evidence