Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein

Guenaga, Javier; Garces, Fernando; de Val, Natalia; Stanfield, Robyn L.; Dubrovskaya, Viktoriya; Higgins, Brett; Carrette, Barbara; Ward, Andrew B.; Wilson, Ian A.; Wyatt, Richard T.

doi:10.1016/j.immuni.2017.04.014

Title: Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein

Journal Article · Mon May 01 00:00:00 EDT 2017 · Immunity

DOI:https://doi.org/10.1016/j.immuni.2017.04.014· OSTI ID:1392744

Guenaga, Javier; Garces, Fernando; de Val, Natalia; Stanfield, Robyn L.; Dubrovskaya, Viktoriya; Higgins, Brett; Carrette, Barbara; Ward, Andrew B.; Wilson, Ian A.; Wyatt, Richard T.

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 Å. 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Cancer Inst.; National Inst. of General Medical Sciences; NIH NIGMS

Grant/Contract Number:: AC02-06CH11357; ACB-12002; AGM-12006; U54 GM094586; UM1 AI00663; P01 HIVRAD AI104722; R56 AI084817

OSTI ID:: 1392744

Alternate ID(s):: OSTI ID: 1368277

Journal Information:: Immunity, Journal Name: Immunity Vol. 46 Journal Issue: 5; ISSN 1074-7613

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 61 works

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Title: Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein

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