CD4-induced activation in a soluble HIV-1 Env trimer

Miklos Guttman; Natalie K Garcia; Albert Cupo; Tsutomu Matsui; Jean-Philippe Julien; Rogier W Sanders; Ian A Wilson; John P Moore; Kelly K Lee

doi:10.1016/j.str.2014.05.001

CD4-induced activation in a soluble HIV-1 Env trimer

Structure. 2014 Jul 8;22(7):974-84. doi: 10.1016/j.str.2014.05.001. Epub 2014 Jun 12.

Authors

Miklos Guttman¹, Natalie K Garcia¹, Albert Cupo², Tsutomu Matsui³, Jean-Philippe Julien⁴, Rogier W Sanders⁵, Ian A Wilson⁴, John P Moore², Kelly K Lee⁶

Affiliations

¹ Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
² Weill Medical College of Cornell University, New York, NY 10021, USA.
³ Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
⁴ 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.
⁵ Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Medical Microbiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁶ Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: kklee@uw.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

CD4 Antigens / chemistry*
CD4 Antigens / metabolism
Deuterium Exchange Measurement
Glycosylation
HEK293 Cells
HIV Envelope Protein gp120 / chemistry
HIV Envelope Protein gp120 / metabolism
HIV Envelope Protein gp41 / chemistry
HIV Envelope Protein gp41 / metabolism
HIV-1 / drug effects
HIV-1 / metabolism
HIV-1 / physiology
Humans
Mass Spectrometry / methods
Models, Molecular
Oxalates / chemistry
Oxalates / metabolism
Oxalates / pharmacology
Piperazines / chemistry
Piperazines / metabolism
Piperazines / pharmacology
Piperidines / chemistry
Piperidines / metabolism
Piperidines / pharmacology
Protein Binding / drug effects
Protein Multimerization*
Protein Structure, Quaternary*
Solubility
env Gene Products, Human Immunodeficiency Virus / chemistry*
env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

BMS 806
CD4 Antigens
HIV Envelope Protein gp120
HIV Envelope Protein gp41
N-(4-chlorophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide
Oxalates
Piperazines
Piperidines
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding