Structural basis of asymmetry in the human immunodeficiency virus type 1 reverse transcriptase heterodimer

Area of Science:

• Biochemistry
• Structural Biology
• Virology

Background:

• Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a key enzyme for viral replication.
• HIV-1 RT is a heterodimer composed of p66 and p51 subunits, derived from proteolytic cleavage of p66.
• The p66 subunit has an open polymerase domain, while the p51 subunit has a closed, compact polymerase domain.

Purpose of the Study:

• To elucidate the structural basis of HIV-1 reverse transcriptase heterodimer formation.
• To investigate the role of the connection subdomain in subunit interactions and conformational changes.
• To propose a model for the asymmetric heterodimer structure and its implications for enzyme function.

Main Methods:

• Comparative structural analysis of p66 and p51 subunits.
• Analysis of intra- and intersubunit contacts within the heterodimer.
• Thermodynamic analysis of conformational changes upon heterodimerization.

Main Results:

• The connection subdomain is crucial for forming extensive intra- and intersubunit contacts, comprising one-third of the heterodimer interactions.
• Conversion from the open p66 to the closed p51 structure buries a significant hydrophobic surface area.
• Monomeric p66 and p51 subunits are proposed to adopt the closed conformation observed in the p51 subunit of the heterodimer.

Conclusions:

• HIV-1 reverse transcriptase heterodimerization involves asymmetric interactions driven by the connection subdomain.
• The formation of the heterodimer stabilizes the enzyme through hydrophobic interactions and conformational changes.
• The study suggests that HIV-1 RT likely forms asymmetric homodimers composed of one open and one closed subunit.