4R61

Crystal structure of a rationally designed single-chain protein mimicking a trimeric gp41 N-terminal heptad-repeat region

Summary for 4R61

• Entry DOI: 10.2210/pdb4r61/pdb
• Descriptor: gp41-based construct covNHR3-ABC (1 entity in total)
• Functional Keywords: coiled-coil, viral protein
• Biological source: Human immunodeficiency virus 1 (HIV-1)
• Total number of polymer chains: 1
• Total formula weight: 20265.14

Authors

Camara-Artigas, A.,Conejero-Lara, F.,Crespillo, S.,Casares, S. (deposition date: 2014-08-22, release date: 2014-12-10, Last modification date: 2023-09-20)

Primary citation

Crespillo, S.,Camara-Artigas, A.,Casares, S.,Morel, B.,Cobos, E.S.,Mateo, P.L.,Mouz, N.,Martin, C.E.,Roger, M.G.,El Habib, R.,Su, B.,Moog, C.,Conejero-Lara, F.
Single-chain protein mimetics of the N-terminal heptad-repeat region of gp41 with potential as anti-HIV-1 drugs.
Proc.Natl.Acad.Sci.USA, 111:18207-18212, 2014

PubMed Abstract: During HIV-1 fusion to the host cell membrane, the N-terminal heptad repeat (NHR) and the C-terminal heptad repeat (CHR) of the envelope subunit gp41 become transiently exposed and accessible to fusion inhibitors or Abs. In this process, the NHR region adopts a trimeric coiled-coil conformation that can be a target for therapeutic intervention. Here, we present an approach to rationally design single-chain protein constructs that mimic the NHR coiled-coil surface. The proteins were built by connecting with short loops two parallel NHR helices and an antiparallel one with the inverse sequence followed by engineering of stabilizing interactions. The constructs were expressed in Escherichia coli, purified with high yield, and folded as highly stable helical coiled coils. The crystal structure of one of the constructs confirmed the predicted fold and its ability to accurately mimic an exposed gp41 NHR surface. These single-chain proteins bound to synthetic CHR peptides with very high affinity, and furthermore, they showed broad inhibitory activity of HIV-1 fusion on various pseudoviruses and primary isolates.

PubMed: 25489108
DOI: 10.1073/pnas.1413592112

Experimental method

X-RAY DIFFRACTION (3.1 Å)