@misc{10481/67927,
year = {2021},
url = {http://hdl.handle.net/10481/67927},
abstract = {A promising strategy to neutralize HIV‐1 is to target the gp41 spike subunit to block
membrane fusion with the cell. We previously designed a series of single‐chain proteins (named
covNHR) that mimic the trimeric coiled‐coil structure of the gp41 N‐terminal heptad repeat (NHR)
region and potently inhibit HIV‐1 cell infection by avidly binding the complementary C‐terminal
heptad repeat (CHR) region. These proteins constitute excellent tools to understand the structural
and thermodynamic features of this therapeutically important interaction. Gp41, as with many
coiled‐coil proteins, contains in core positions of the NHR trimer several highly conserved, buried
polar residues, the role of which in gp41 structure and function is unclear. Here we produced three
covNHR mutants by substituting each triad of polar residues for the canonical isoleucine. The
mutants preserve their helical structure and show an extremely increased thermal stability. How‐
ever, increased hydrophobicity enhances their self‐association. Calorimetric analyses show a
marked influence of mutations on the binding thermodynamics of CHR‐derived peptides. The
mutations do not affect however the in vitro HIV‐1 inhibitory activity of the proteins. The results
support a role of buried core polar residues in maintaining structural uniqueness and promoting
an energetic coupling between conformational stability and NHR–CHR binding},
publisher = {MDPI},
keywords = {HIV},
keywords = {AIDS},
keywords = {Envelope glycoprotein},
keywords = {Stability},
keywords = {Fusion inhibitors},
keywords = {Calorimetry},
keywords = {Peptides},
keywords = {Binding},
title = {Extremely Thermostabilizing Core Mutations in Coiled‐Coil Mimetic Proteins of HIV‐1 gp41 Produce Diverse Effects on Target Binding but Do Not Affect Their Inhibitory Activity},
doi = {10.3390/biom 11040566},
author = {Cano Muñoz, Mario and Cesaro, Samuele and Morel, Bertrand and Conejero Lara, Francisco},
}