The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site.

Jérémie Prévost,Beatrice H Hahn,Cameron F Abrams,Daria Zoubchenok,Melissa C Grenier,Marzena Pazgier,Amos B Smith,Brendan T Mann,Sharon Kirk,Hillel Haim,Andrés Finzi,Halima Medjahed,Frank Kirchhoff,Changze Han,Navid Madani,Joseph Sodroski,Agnès Laurence Chenine ,Adel Ahmed Rashad Ahmed ,Rebekah Sherburn ,Althea Gaffney ,Irwin M Chaiken ,Natasha Gupta Vergara ,Gabrielle Gendron‐Lepage ,W.d Tolbert

doi:10.1128/mbio.00280-20

Abstract

The HIV-1 envelope glycoproteins (Env) undergo conformational changes upon interaction of the gp120 exterior glycoprotein with the CD4 receptor. The gp120 inner domain topological layers facilitate the transition of Env to the CD4-bound conformation. CD4 engages gp120 by introducing its phenylalanine 43 (Phe43) in a cavity ("the Phe43 cavity") located at the interface between the inner and outer gp120 domains. Small CD4-mimetic compounds (CD4mc) can bind within the Phe43 cavity and trigger conformational changes similar to those induced by CD4. Crystal structures of CD4mc in complex with a modified CRF01_AE gp120 core revealed the importance of these gp120 inner domain layers in stabilizing the Phe43 cavity and shaping the CD4 binding site. Our studies reveal a complex interplay between the gp120 inner domain and the Phe43 cavity and generate useful information for the development of more-potent CD4mc.IMPORTANCE The Phe43 cavity of HIV-1 envelope glycoproteins (Env) is an attractive druggable target. New promising compounds, including small CD4 mimetics (CD4mc), were shown to insert deeply into this cavity. Here, we identify a new network of residues that helps to shape this highly conserved CD4 binding pocket and characterize the structural determinants responsible for Env sensitivity to small CD4 mimetics.

Highlights

The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) undergo conformational changes upon interaction of the gp120 exterior glycoprotein with the CD4 receptor
Env-CD4 complexes at the surface of HIV-1-infected cells were previously shown to be efficiently recognized by CD4-induced (CD4i) Abs, which are present in sera from HIV-1-infected individuals and can mediate potent antibody-dependent cellular cytotoxicity (ADCC) responses [24,25,26,27,28]
We previously reported that six residues within the gp120 inner domain layers coevolved with phenylalanine 43 (Phe43) cavity residue 375 to facilitate CD4 interaction [41]

Summary

Introduction

The HIV-1 envelope glycoproteins (Env) undergo conformational changes upon interaction of the gp120 exterior glycoprotein with the CD4 receptor. Small CD4-mimetic compounds (CD4mc) can bind within the Phe cavity and trigger conformational changes similar to those induced by CD4. Crystal structures of CD4mc in complex with a modified CRF01_AE gp120 core revealed the importance of these gp120 inner domain layers in stabilizing the Phe cavity and shaping the CD4 binding site. Layer 3 was previously shown to govern the efficiency of the initial gp120 interaction with CD4, a function that can be fulfilled by filling the Phe cavity with a bulky residue at position 375 [13, 14, 17]. Env-CD4 complexes at the surface of HIV-1-infected cells were previously shown to be efficiently recognized by CD4-induced (CD4i) Abs, which are present in sera from HIV-1-infected individuals and can mediate potent antibody-dependent cellular cytotoxicity (ADCC) responses [24,25,26,27,28]. In silico, and functional analyses, using CD4mc as probes, we uncovered how the gp120 inner domain shapes the Phe cavity and the CD4 binding site

Methods

Results

Conclusion