@article{1ef05ff6a3f14bde8e1003171a77b10f,
title = "Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein",
abstract = "Advances in HIV-1 envelope glycoprotein (Env) design generate native-like trimers and high-resolution clade A, B, and G structures and elicit neutralizing antibodies. However, a high-resolution clade C structure is critical, as this subtype accounts for the majority of HIV infections worldwide, but well-ordered clade C Env trimers are more challenging to produce due to their instability. Based on targeted glycine substitutions in the Env fusion machinery, we defined a general approach that disfavors helical transitions leading to post-fusion conformations, thereby favoring the pre-fusion state. We generated a stabilized, soluble clade C Env (16055 NFL) and determined its crystal structure at 3.9 {\AA}. Its overall conformation is similar to SOSIP.664 and native Env trimers but includes a covalent linker between gp120 and gp41, an engineered 201-433 disulfide bond, and density corresponding to 22 N-glycans. Env-structure-guided design strategies resulted in multiple homogeneous cross-clade immunogens with the potential to advance HIV vaccine development.",
keywords = "Antibody, Envelope glycoprotein, Glycan shield, HIV, Immunogen, Trimer, Vaccine, bNAb",
author = "Javier Guenaga and Fernando Garces and {de Val}, Natalia and Stanfield, {Robyn L.} and Viktoriya Dubrovskaya and Brett Higgins and Barbara Carrette and Ward, {Andrew B.} and Wilson, {Ian A.} and Wyatt, {Richard T.}",
note = "Funding Information: This work was supported by the International AIDS Vaccine Initiative Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD OPP1084519) (J.G., I.A.W., A.B.W., and R.T.W.). IAVI's work is made possible by generous support from many donors, including the following: the Bill & Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at www.iavi.org. We are very grateful to H. Tien for crystallization screening. X-ray data sets were collected at the GM/CA@APS-23ID-D beamline, which has been funded in whole or in part with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. This work was supported by the Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) UM1 AI00663 (A.B.W., I.A.W., and R.T.W.), by NIH P01 HIVRAD AI104722 (R.T.W.), by NIH R56 AI084817 (I.A.W.) and by the Joint Center of Structural Genomics (JCSG) funded by the NIH NIGMS Protein Structure Initiative U54 GM094586 (I.A.W.). Publisher Copyright: {\textcopyright} 2017 The Author(s)",
year = "2017",
month = may,
day = "16",
doi = "10.1016/j.immuni.2017.04.014",
language = "English (US)",
volume = "46",
pages = "792--803.e3",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "5",
}