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

Immunity
Javier GuenagaRichard T Wyatt

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 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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Citations

Apr 14, 2018·Acta Crystallographica. Section D, Structural Biology·Paul Emsley, Max Crispin
Dec 13, 2017·Frontiers in Immunology·Martina SoldemoGunilla B Karlsson Hedestam
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Datasets Mentioned

BETA
DQ388515

Methods Mentioned

BETA
size
immunoprecipitation
differential scanning calorimetry
glycosylation
Bio-layer interferometry
PCR
transfection
size exclusion chromatography
X-ray

Software Mentioned

Coot
msa
refine
2000
IMAGIC
phenix
HKL
DoG Picker
mra Clustering
ForteBio

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