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 CD4-bound conformation. CD4 engages gp120 by introducing its phe...

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Autores principales:	Jérémie Prévost, William D. Tolbert, Halima Medjahed, Rebekah T. Sherburn, Navid Madani, Daria Zoubchenok, Gabrielle Gendron-Lepage, Althea E. Gaffney, Melissa C. Grenier, Sharon Kirk, Natasha Vergara, Changze Han, Brendan T. Mann, Agnès L. Chénine, Adel Ahmed, Irwin Chaiken, Frank Kirchhoff, Beatrice H. Hahn, Hillel Haim, Cameron F. Abrams, Amos B. Smith, Joseph Sodroski, Marzena Pazgier, Andrés Finzi
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Env gp120 CD4 CD4mc CRF01_AE ADCC Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c4fa9bf5772f469680b5dab67aad98e5
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spelling	oai:doaj.org-article:c4fa9bf5772f469680b5dab67aad98e52021-11-15T15:56:46ZThe HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site10.1128/mBio.00280-202150-7511https://doaj.org/article/c4fa9bf5772f469680b5dab67aad98e52020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00280-20https://doaj.org/toc/2150-7511ABSTRACT 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.Jérémie PrévostWilliam D. TolbertHalima MedjahedRebekah T. SherburnNavid MadaniDaria ZoubchenokGabrielle Gendron-LepageAlthea E. GaffneyMelissa C. GrenierSharon KirkNatasha VergaraChangze HanBrendan T. MannAgnès L. ChénineAdel AhmedIrwin ChaikenFrank KirchhoffBeatrice H. HahnHillel HaimCameron F. AbramsAmos B. SmithJoseph SodroskiMarzena PazgierAndrés FinziAmerican Society for MicrobiologyarticleEnvgp120CD4CD4mcCRF01_AEADCCMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Env gp120 CD4 CD4mc CRF01_AE ADCC Microbiology QR1-502
spellingShingle	Env gp120 CD4 CD4mc CRF01_AE ADCC Microbiology QR1-502 Jérémie Prévost William D. Tolbert Halima Medjahed Rebekah T. Sherburn Navid Madani Daria Zoubchenok Gabrielle Gendron-Lepage Althea E. Gaffney Melissa C. Grenier Sharon Kirk Natasha Vergara Changze Han Brendan T. Mann Agnès L. Chénine Adel Ahmed Irwin Chaiken Frank Kirchhoff Beatrice H. Hahn Hillel Haim Cameron F. Abrams Amos B. Smith Joseph Sodroski Marzena Pazgier Andrés Finzi The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
description	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.
format	article
author	Jérémie Prévost William D. Tolbert Halima Medjahed Rebekah T. Sherburn Navid Madani Daria Zoubchenok Gabrielle Gendron-Lepage Althea E. Gaffney Melissa C. Grenier Sharon Kirk Natasha Vergara Changze Han Brendan T. Mann Agnès L. Chénine Adel Ahmed Irwin Chaiken Frank Kirchhoff Beatrice H. Hahn Hillel Haim Cameron F. Abrams Amos B. Smith Joseph Sodroski Marzena Pazgier Andrés Finzi
author_facet	Jérémie Prévost William D. Tolbert Halima Medjahed Rebekah T. Sherburn Navid Madani Daria Zoubchenok Gabrielle Gendron-Lepage Althea E. Gaffney Melissa C. Grenier Sharon Kirk Natasha Vergara Changze Han Brendan T. Mann Agnès L. Chénine Adel Ahmed Irwin Chaiken Frank Kirchhoff Beatrice H. Hahn Hillel Haim Cameron F. Abrams Amos B. Smith Joseph Sodroski Marzena Pazgier Andrés Finzi
author_sort	Jérémie Prévost
title	The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
title_short	The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
title_full	The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
title_fullStr	The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
title_full_unstemmed	The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
title_sort	hiv-1 env gp120 inner domain shapes the phe43 cavity and the cd4 binding site
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/c4fa9bf5772f469680b5dab67aad98e5
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The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site

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