Journal article
The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
mBio, v 11(3), pe00280-20
26 May 2020
PMID: 32457241
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
Metrics
Details
- Title
- The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site
- Creators
- Jérémie Prévost - Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, CanadaWilliam D Tolbert - Infectious Diseases Division, Department of Medicine of Uniformed Services, University of the Health Sciences, Bethesda, Maryland, USAHalima Medjahed - Centre de Recherche du CHUM, Montreal, Quebec, CanadaRebekah T Sherburn - Infectious Diseases Division, Department of Medicine of Uniformed Services, University of the Health Sciences, Bethesda, Maryland, USANavid Madani - Department of Microbiology, Harvard Medical School, Boston, Massachusetts, USADaria Zoubchenok - Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, CanadaGabrielle Gendron-Lepage - Centre de Recherche du CHUM, Montreal, Quebec, CanadaAlthea E Gaffney - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USAMelissa C Grenier - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USASharon Kirk - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USANatasha Vergara - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAChangze Han - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USABrendan T Mann - Henry M. Jackson Foundation for the Advancement of the Military Medicine, Bethesda, Maryland, USAAgnès L Chénine - Henry M. Jackson Foundation for the Advancement of the Military Medicine, Bethesda, Maryland, USAAdel Ahmed - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAIrwin Chaiken - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAFrank Kirchhoff - Institute of Molecular Virology, Ulm University Medical Center, Ulm, GermanyBeatrice H Hahn - Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USAHillel Haim - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USACameron F Abrams - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAAmos B Smith, 3rd - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USAJoseph Sodroski - Department of Microbiology, Harvard Medical School, Boston, Massachusetts, USAMarzena Pazgier - Infectious Diseases Division, Department of Medicine of Uniformed Services, University of the Health Sciences, Bethesda, Maryland, USAAndrés Finzi - Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
- Publication Details
- mBio, v 11(3), pe00280-20
- Publisher
- American Society for Microbiology (ASM); United States
- 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 R33 AI129017 / NIAID NIH HHS R01 AI129769 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Chemical and Biological Engineering
- Web of Science ID
- WOS:000572051800005
- Scopus ID
- 2-s2.0-85085538725
- Other Identifier
- 991014969864104721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology