title: CD4-induced activation in a soluble HIV-1 Env trimer.
abstract: The HIV envelope glycoprotein (Env) trimer undergoes receptor-induced conformational changes that drive fusion of the viral and cellular membranes. Env conformational changes have been observed using low-resolution electron microscopy, but only large-scale rearrangements have been visible. Here, we use hydrogen-deuterium exchange and oxidative labeling to gain a more precise understanding of the unliganded and CD4-bound forms of soluble Env trimers (SOSIP.664), including their glycan composition. CD4 activation induces the reorganization of bridging sheet elements, V1/V2 and V3, much of the gp120 inner domain, and the gp41 fusion subunit. Two CD4 binding site-targeted inhibitors have substantially different effects: NBD-556 partially mimics CD4-induced destabilization of the V1/V2 and V3 crown, whereas BMS-806 only affects regions around the gp120/gp41 interface. The structural information presented here increases our knowledge of CD4- and small molecule-induced conformational changes in Env and the allosteric pathways that lead to membrane fusion.
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Miklos
authors.initials: M
authors.lastname: Guttman
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Garcia
authors.affiliation: Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Cupo
authors.affiliation: Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Julien
authors.affiliation: Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.affiliation: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.affiliation: Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: kklee@uw.edu.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Lee
mesh_terms: D015704:CD4 Antigens / Q000737:chemistry* / Q000378:metabolism; D041961:Deuterium Exchange Measurement; D006031:Glycosylation; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D008958:Models, Molecular; D010070:Oxalates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012995:Solubility; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000378:metabolism
chemical_list: C451732:BMS 806; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C514246:N-(4-chlorophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide; D010070:Oxalates; D010879:Piperazines; D010880:Piperidines; D054299:env Gene Products, Human Immunodeficiency Virus