Computational Refinement and Validation Protocol for Proteins with Large Variable Regions Applied to Model HIV Env Spike in CD4 and 17b Bound State

Structure. 2015 Jun 2;23(6):1138-49. doi: 10.1016/j.str.2015.03.026.

Abstract

Envelope glycoprotein gp120 of HIV-1 possesses several variable regions; their precise structure has been difficult to establish. We report a new model of gp120, in complex with antibodies CD4 and 17b, complete with its variable regions. The model was produced by a computational protocol that uses cryo-electron microscopy (EM) maps, atomic-resolution structures of the core, and information on binding interactions. Our model has excellent fit with EMD: 5020, is stereochemically and energetically favorable, and has the expected binding interfaces. Comparison of the ternary arrangement of the loops in this model with those bound to PGT122 and PGV04 suggested a possible motion of the V1V2 away from the CCR5 binding site and toward CD4. Our study also revealed that the CD4-bound state of the V1V2 loop is not optimal for gp120 bound with several neutralizing antibodies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Neutralizing / metabolism
  • CD4 Antigens / chemistry
  • CD4 Antigens / metabolism*
  • Cryoelectron Microscopy
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / metabolism*
  • Models, Molecular*
  • Protein Binding
  • Protein Conformation

Substances

  • Antibodies, Neutralizing
  • CD4 Antigens
  • HIV Envelope Protein gp120

Associated data

  • PDB/3J70