crystal structure of hiv-1 gp41 including both fusion peptide and membrane proximal external regions晶体结构的hiv - 1 gp41包括融合肽和膜近端外部区域.pdf

Crystal Structure of HIV-1 gp41 Including Both Fusion Peptide and Membrane Proximal External Regions Victor Buzon1., Ganesh Natrajan 1., David Schibli1¤, Felix Campelo2, Michael M. Kozlov2, Winfried Weissenhorn1* ´ 1 Unit of Virus Host Cell Interactions (UVHCI) UMI 3265 Universite Joseph Fourier-EMBL-CNRS, Grenoble, France, 2 Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Abstract The HIV-1 envelope glycoprotein (Env) composed of the receptor binding domain gp120 and the fusion protein subunit gp41 catalyzes virus entry and is a major target for therapeutic intervention and for neutralizing antibodies. Env interactions with cellular receptors trigger refolding of gp41, which induces close apposition of viral and cellular membranes leading to membrane fusion. The energy released during refolding is used to overcome the kinetic barrier and drives the fusion ˚ reaction. Here, we report the crystal structure at 2 A resolution of the complete extracellular domain of gp41 lacking the fusion peptide and the cystein-linked loop. Both the fusion peptide proximal region (FPPR) and the membrane proximal external region (MPER) form helical extensions from the gp41 six-helical bundle core structure. The lack of regular coiled-coil interactions within FPPR and MPER splay this end of the structure apart while positioning the fusion peptide towards the outside of the six-helical bundle and exposing conserved hydrophobic MPER residues. Unexpectedly, the section of the MPER, which is juxtaposed to the transmembrane region (TMR), bends in a 90u-angle sid