Journal article
The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
mBio, Vol.11(3), pp.1-26
05/26/2020
DOI: 10.1128/MBIO.00280-20
PMCID: PMC7251204
PMID: 32457241
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.
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.
Details
- Title: Subtitle
- The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
- Creators
- Jérémie Prévost - Université de MontréalWilliam D Tolbert - Uniformed Services University of the Health SciencesHalima Medjahed - Centre Hospitalier de l’Université de MontréalRebekah T Sherburn - Uniformed Services University of the Health SciencesNavid Madani - Harvard UniversityDaria Zoubchenok - Université de MontréalGabrielle Gendron-Lepage - Centre Hospitalier de l’Université de MontréalAlthea E Gaffney - University of PennsylvaniaMelissa C Grenier - University of PennsylvaniaSharon Kirk - University of PennsylvaniaNatasha Vergara - Drexel UniversityChangze Han - University of IowaBrendan T Mann - Walter Reed Army Institute of ResearchAgnès L Chénine - Walter Reed Army Institute of ResearchAdel Ahmed - Drexel UniversityIrwin Chaiken - Drexel UniversityFrank Kirchhoff - Universität UlmBeatrice H Hahn - University of PennsylvaniaHillel Haim - University of IowaCameron F Abrams - Drexel UniversityAmos B Smith III - University of PennsylvaniaJoseph Sodroski - Harvard UniversityMarzena Pazgier - Uniformed Services University of the Health SciencesAndrés Finzi - Université de Montréal
- Resource Type
- Journal article
- Publication Details
- mBio, Vol.11(3), pp.1-26
- DOI
- 10.1128/MBIO.00280-20
- PMID
- 32457241
- PMCID
- PMC7251204
- NLM abbreviation
- mBio
- ISSN
- 2161-2129
- eISSN
- 2150-7511
- Grant note
- P01 AI131251 / NIAID NIH HHS R01 AI124982 / NIAID NIH HHS P01 AI150471 / NIAID NIH HHS U01 AI150741 / NIAID NIH HHS P01 GM056550 / NIGMS NIH HHS R01 AI145547 / NIAID NIH HHS R01 AI116274 / NIAID NIH HHS 352417 / CIHR R37 AI150590 / NIAID NIH HHS R33 AI129017 / NIAID NIH HHS R01 AI129769 / NIAID NIH HHS
- Language
- English
- Date published
- 05/26/2020
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984297427702771
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