Three-dimensional structure of the palbociclib-HIV TAR complex.

Area of Science:

• Structural Biology
• Molecular Biology
• Virology

Background:

• The HIV-1 transactivation response (TAR) element is crucial for viral gene expression.
• Understanding TAR-small molecule interactions is key for developing antiviral therapies.
• Palbociclib is a known kinase inhibitor with potential antiviral applications.

Purpose of the Study:

• To elucidate the structural basis of HIV-1 TAR element binding by palbociclib.
• To investigate how palbociclib induces structural changes in the TAR element.
• To explore the implications of these structural changes for RNA-small molecule interactions.

Main Methods:

• X-ray crystallography to determine the structure of TAR-palbociclib complex.
• RNA mutagenesis to probe the functional significance of structural features.
• Biochemical assays to assess binding affinity and disruption of interactions.

Main Results:

• Palbociclib binding induces significant rearrangement of the TAR element, forming a deep binding pocket.
• A novel "intermolecular pair" between U40 and displaced A22 is formed, extending the helical structure.
• Three new base triples involving bulge nucleotides stabilize the altered RNA conformation.
• Mutations or drug modifications disrupting binding also abolish key intermolecular contacts.

Conclusions:

• Small molecule binding can induce extensive RNA refolding, creating specific and potent interactions.
• The observed RNA refolding is critical for eliciting a biochemical response.
• The unique structural requirements suggest high specificity for this interaction within the transcriptome.