@article{89add5e2bce54a4dbb9109383473503b,
title = "The HIV-1 ENV GP120 inner domain shapes the PHE43 cavity and the CD4 binding site",
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 CD4bound 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.",
keywords = "ADCC, CD4, CD4 binding site, CD4 mimetic, CD4mc, CRF01_AE, Env, Gp120, HIV-1, Neutralization, Phe43 cavity",
author = "J{\'e}r{\'e}mie Pr{\'e}vost and Tolbert, {William D.} and Halima Medjahed and Sherburn, {Rebekah T.} and Navid Madani and Daria Zoubchenok and Gabrielle Gendron-Lepage and Gaffney, {Althea E.} and Grenier, {Melissa C.} and Sharon Kirk and Natasha Vergara and Changze Han and Mann, {Brendan T.} and Ch{\'e}nine, {Agn{\`e}s L.} and Adel Ahmed and Irwin Chaiken and Frank Kirchhoff and Hahn, {Beatrice H.} and Hillel Haim and Abrams, {Cameron F.} and Smith, {Amos B.} and Joseph Sodroski and Marzena Pazgier and Andr{\'e}s Finzi",
note = "Funding Information: This work was supported by CIHR foundation grant 352417 to A.F. Support for this work was also provided by NIH R01 to A.F. and M.P. (AI129769) and J.S. (AI124982 and AI145547) and by NIAID R01 to M.P. (AI116274). This study was also supported by NIH R01-GM56550 to A.B.S. and by grant P01-GM56550/AI150741 to A.F., A.B.S., I.C., J.S., and C.F.A. A.F. is the recipient of a Canada Research Chair on Retroviral Entry RCHS0235. J.P. is the recipient of a CIHR doctoral fellowship. C.H. was supported by a Development Grant from the University of Iowa (MI-2019). F.K. is supported by grants from the DFG (CRC 1279 and SPP 1923). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Uniformed Services University, U.S. Army, the Department of Defense, or the U.S. Government. Publisher Copyright: {\textcopyright} 2020 Pr{\'e}vost et al.",
year = "2020",
doi = "10.1128/MBIO.00280-20",
language = "English",
volume = "11",
pages = "1--26",
journal = "mBio",
issn = "2161-2129",
number = "3",
}