Structural basis of coreceptor recognition by HIV-1 envelope spike

Area of Science:

• Structural Biology
• Virology
• Immunology

Background:

• HIV-1 entry relies on envelope glycoprotein (Env) interaction with CD4 and coreceptors like CCR5.
• The gp120-coreceptor binding is critical for triggering viral fusion via gp41.
• Understanding this interaction is key for developing HIV therapies and vaccines.

Purpose of the Study:

• To determine the high-resolution structure of HIV-1 gp120 in complex with CD4 and CCR5.
• To elucidate the molecular mechanism by which CCR5 binding initiates viral fusion.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to obtain a 3.9 Å resolution structure.
• The study analyzed the interaction between full-length gp120, soluble CD4, and unmodified human CCR5.

Main Results:

• The V3 loop of gp120 inserts into the CCR5 chemokine-binding pocket.
• CCR5 binding does not cause allosteric changes in gp120 but brings Env closer to the target membrane.
• The N terminus of gp120 flips, potentially destabilizing gp41 and initiating fusion.

Conclusions:

• CCR5 acts as a stabilizing anchor for the CD4-bound Env conformation near the cell membrane.
• The findings provide crucial insights into the HIV-1 entry pathway.
• This structural understanding may inform the design of novel HIV vaccines and therapeutics.